Europe/Asia USA
Bachem AG Bachem Americas, Inc.
Hauptstrasse 144 3132 Kashiwa Street
4416 Bubendorf - Switzerland Torrance, CA 90505 - USA
Tel +41 61 935 2323 Tel +1 888 422 2436
Fax +41 61 935 2325 +1 888 4BACHEM
E-mail sales.ch@bachem.com +1 310 539 4171
  Fax +1 310 539 9428
  E-mail sales.us@bachem.com

PEPTIDE TRENDS OCTOBER 2017

MEET US AT CPHI WORLDWIDE

Bachem is participating in the CPhI Worldwide the world’s leading pharmaceutical platform. The 2017 edition will take place on October 24 - 26, 2017 in Frankfurt, Germany together with co-located events ICSE, InnoPack, P-MEC and FDF and hosting more than 42,000 visiting pharma professionals over three days.

 

We look forward to meet our partners and discuss how Bachem can help with their generic API manufacturing needs. In addition to more than 45 years of experience in the manufacture of drug substance, Bachem also has a strong regulatory background and we are well prepared to fully support you with the required regulatory documentation. Bachem is your trusted supplier of peptide and small molecule generics.

 

We invite you to visit us at the Messe Frankfurt, Hall 8, Booth #80C52: please contact us to schedule a meeting in advance.

 

You are kindly invited to attend the seminar Pharma Insight Briefings. Michael Postlethwaite, Ph.D., Business Development Manager, Bachem AG will present “An Approach to Process Risk Mitigation by FMEA” on October 24, 2017, Pharma Forum Galleria, Hall 8, at 3.50 p.m.

 

We look forward to meeting you at CPhI Worldwide 2017!

PEPTIDES IN DIABETES

According to data from the International Diabetes Federation, more than 400 million adults aged 20-79 around the world suffered from diabetes in 2015. This alarming number could reach 640 million by 2040. Further 318 million people have impaired glucose tolerance, a condition that can signal oncoming diabetes. In high-income countries, approximately 87% to 91% of all people with diabetes have type 2 diabetes, a chronic disease associated with insulin deficiency and insulin resistance. Complications seen with diabetes range from heart disease to blindness, kidney disease, amputations, nerve damage and erectile dysfunction. As obesity spreads, the number of type 2 diabetics rises. Over 80% of diabetics are obese. Consequently, the treatment of risk factors such as obesity, hypertension, and hyperlipidemia assumes major importance and must be coordinated with a good glycemic control for the reduction in total mortality in type 2 diabetes mellitus.

 

Pancreatic Peptide Hormones

The islets of Langerhans contain four main cell types: β-cells secreting insulin, α-cells secreting glucagon, δ-cells secreting somatostatin and γ-cells secreting pancreatic polypeptide (PP). The core of each islet contains mainly the β-cells surrounded by a mantle of α-cells interspersed with δ-cells or γ-cells. Insulin is synthesized as a preprohormone in the β-cells of the islets of Langerhans. Within the endoplasmic reticulum proinsulin is exposed to several specific endopeptidases. These enzymes excise the C-peptide, thereby generating the mature form of insulin. β-Cells secrete insulin in response to a rising level of circulating glucose. After a meal, excess sugars must be stored so that energy reserves will be available later on. Excess glucose is sensed by β-cells in the pancreas, which respond by secreting insulin into the bloodstream. Insulin causes various cells in the body to store glucose (see Fig. 1):

• Insulin stimulates skeletal muscle fibers to convert glucose into glycogen. It also induces the synthesis of proteins from amino acids circulating in the blood.

• Insulin acts on liver cells. It stimulates them to take up glucose from the blood converting it into glycogen while inhibiting the production of the enzymes involved in glycogenolysis.

• Insulin acts on fat cells to stimulate the uptake of glucose and the synthesis of fat. In each case, insulin triggers these effects by binding to the insulin receptor. Insulin receptor activation leads to specific phosphorylation events followed by an increase in glucose storage and a concomitant decrease in hepatic glucose release.

 

β-Cells also secrete a peptide hormone known as islet amyloid polypeptide (IAPP) or amylin. It is stored together with insulin in the secretory granules of β-cells and is co-secreted with insulin. Amylin’s most potent actions include the slowing of gastric emptying and the suppression of postprandial glucagon secretion. The hormone also reduces food intake and inhibits the secretion of gastric acid and digestive enzymes. Glucagon secretion is stimulated by low, and inhibited by high concentrations of glucose and fatty acids in the plasma (see Fig. 1). It counterbalances the action of insulin, increasing the levels of blood glucose and stimulating the protein breakdown in muscle. Glucagon is a major catabolic hormone, acting primarily on the liver. The peptide stimulates glycogenolysis (glycogen breakdown) and gluconeogenesis (synthesis of glucose from non-carbohydrate sources), inhibits glycogenesis (glycogen synthesis) and glycolysis, overall increasing hepatic glucose output and ketone body formation. In people suffering from diabetes, excess secretion of glucagon plays a primary role in hyperglycemia (high blood glucose concentration).

 

 

Figure 1: Opposing effects of insulin and glucagon

 

Gastrointestinal Peptide Hormones

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have significant effects on insulin secretion and glucose regulation. They are released after ingestion of carbohydrate- and fat-rich meals and stimulate insulin secretion postprandially. Both gut hormones constitute the class of incretins and share considerable sequence homology. GIP was originally observed to inhibit gastric acid secretion (hence it was designated gastric inhibitory polypeptide). Subsequent studies have demonstrated potent glucose-dependent insulin stimulatory effects of GIP administration in dogs and rodents. GIP also regulates fat metabolism in adipocytes, including stimulation of lipoprotein lipase activity, fatty acid incorporation, and fatty acid synthesis. Unlike GLP-1, GIP does not inhibit glucagon secretion or gastric emptying. The peptide promotes β-cell proliferation and cell survival in islet cell line studies.

GLP-1 is derived from the product of the proglucagon gene. This gene encodes a preproprotein (see Fig. 2) that is differentially processed dependent on the tissue in which it is expressed. In pancreatic α-cells, prohormone convertase 2 action leads to the release of glucagon. In the gut, prohormone convertase 1/3 action leads to the release of several peptides including GLP- 1. Bioactive GLP-1 consists of two forms: GLP-1 (7-37) and GLP-1 (7-36) amide. The latter form constitutes the majority (80%) of the circulating GLPs. The primary physiological responses to GLP-1 are glucose-dependent insulin secretion, inhibition of glucagon secretion and inhibition of gastric acid secretion and gastric emptying.

 

 

Figure 2: Structure of preproglucagon

 

Classification of Diabetes Mellitus

The International Diabetes Federation distinguishes between three main types of diabetes mellitus. This division is based upon whether the ‘blood sugar problem‘ is caused by insulin deficiency or insulin resistance: Type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is a β-islet cell specific, T-lymphocyte-mediated autoimmune disorder. It is characterized by a failure of the pancreas to produce sufficient insulin. The classic symptoms are excessive secretion of urine, thirst, weight loss and tiredness. Type 2 diabetes (formerly named non-insulin-dependent diabetes mellitus or maturity-onset diabetes) is associated with insulin resistance rather than the lack of insulin as seen in type 1 diabetes. This lack of insulin sensitivity results in higher than normal blood glucose levels. The development of type 2 diabetes seems to be multifactorial. Genetic predisposition appears to be the strongest factor. Other risk factors are obesity and high caloric intake. Type 2 diabetes occurs most frequently in adults, but is being noted increasingly in adolescents as well. Type 2 diabetes develops slowly and the symptoms are usually less severe than in type 1. Gestational diabetes may be observed in non-diabetic women during late pregnancy. They develop a resistance to insulin and, subsequently, high blood glucose. This type of diabetes is probably caused by hormones produced by the placenta. The blood glucose level has to be carefully controlled as to minimize risks for mother and child, it will return to the normal value after birth.

 

Treatment of Diabetes Mellitus

Insulin is essential for the treatment of type 1 diabetes. Today, human insulin (produced recombinantly) is used. Most of the vascular consequences of insulin resistance are due to the hyperglycemia seen in type 2 diabetes. For this reason a major goal of therapeutic intervention in type 2 diabetes is to reduce circulating glucose levels. There are many pharmacological strategies to accomplish these goals:

1) The use of α-glucosidase inhibitors (e.g. acarbose) leads to a reduction in digestion and thereby minimizes the consequent absorption of glucose into the systemic circulation. The reduction in glucose uptake allows the pancreatic β-cells to regulate the insulin secretion more effectively. The advantage of α-glucosidase inhibitors is that they function locally in the intestine and have no major systemic action.

2) The sulfonylureas (e.g. glibenclamide) are referred to as endogenous insulin secretagogues because they induce the pancreatic release of insulin and thus reduce plasma glucose. Sulfonylureas function by binding to and inhibiting the pancreatic ATP-dependent potassium channels normally involved in the glucose-mediated insulin secretion.

3) The biguanides (e.g. metformin) are a class of drugs that lower blood glucose levels by enhancing insulin-mediated suppression of hepatic glucose production (gluconeogenesis) and by enhancing insulin-stimulated glucose uptake by skeletal muscle.

4) The thiazolidinediones (e.g. pioglitazone) have been proven useful in treating the hyperglycemia associated with insulin resistance in both type 2 diabetes and non-diabetic conditions. These products function as agonists for the peroxisome proliferator-activated receptor-γ (PPAR-γ). Thiazolidinediones enhance peripheral sensitivity to insulin and, to a lesser degree, decrease hepatic glucose production by binding to and activating the PPAR-γ.

5) GLP-1 analogs stimulate insulin release, inhibit glucagon secretion, slow gastric emptying and stimulate β-cell proliferation. One of the most promising GLP-1 receptor agonists is exenatide (exendin-4) which is 53% identical to human GLP-1 at the amino acid level. The main advantage of exenatide is its resistance to cleavage and inactivation by dipeptidyl-peptidase IV (DPP IV).

6) DPP IV inhibitors represent another approach for the treatment of diabetes. Sitagliptin is the first candidate of this novel class of antihyperglycemic agents that has been approved by the FDA. Alogliptin, linagliptin, saxagliptin, and vildagliptin have been approved in the USA and in various countries worldwide. These DPP IV inhibitors can be used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type 2.

7) Pramlintide, a soluble amylin analog, has gained FDA approval as an adjunct to insulin therapy in type 1 and type 2 diabetes. Like amylin, pramlintide acts centrally and decreases glucagon secretion, slows gastric emptying and induces satiety.

8) Insulin therapy is also indicated in the treatment of type 2 diabetes for the management of severe hyperglycemia after failure of oral agents.

9) C-Peptide is biologically active. Clinical studies showed that administration of C-peptide to diabetes type 1 patients lacking the peptide alleviates nerve and renal dysfunctions associated with the disease.

 

Prospects

Although some of the agents described above are still in the early phases of investigation, there is little doubt that the therapy of diabetes will undergo major changes in the near future. It is important to diagnose all type 2 diabetics at an earlier stage (for example by making self monitoring of blood glucose easier) and begin treatment in an attempt to minimize the diabetes-associated complications. The identification of the genetic components of type 1 and type 2 diabetes is an important area of research, because elucidation of the diabetes genes will influence all efforts towards an understanding of the disease, its complications, and its treatment, cure, and prevention. For this reason, genomic DNA from subjects with severe insulin resistance has been screened for mutations in genes that are implicated in insulin signaling. Indeed, a mutation in the gene encoding the serine/threonine kinase AKT2 (also known as PKBβ) could be identified. AKT2 is highly expressed in insulin-sensitive tissues and has been implicated in insulin-regulated glucose uptake into muscle and fat cells by promoting the translocation of glucose transporter 4 (GLUT4) to the cell surface. Advances in genomics, proteomics and metabolomics will help us to further understand the causes of type 1 and type 2 diabetes and could eventually lead to novel therapeutic approaches.

 

References

Product Monograph Diabetes Peptides

 

Explore our broad offering of diabetes peptides

Products for Diabetes Research in our Online Shop

PEPTIDE DRUGS IN CLINICAL DEVELOPMENT FOR TYPE 2 DIABETES

There are many peptide drug candidates advancing through clinical development for the treatment of type 2 diabetes. GLP-1 receptor agonists, also known as incretin mimetics, are attractive for the treatment of type 2 diabetes because they offer glycemic control with a low risk of hypoglycemia. In addition, clinical data has shown that some GLP-1 receptor agonists have other benefits such as promoting weight loss or reducing systolic blood pressure (1). Several GLP-1 receptor agonists are already approved for the treatment of type 2 diabetes including Victoza® (liraglutide), Byetta® (exenatide) and Bydureon® (exenatide), Lyxumia® (lixisenatide), Trulicity® (dulaglutide), and Syncria® (albiglutide). Efforts are underway to optimize the potential of GLP-1 receptor agonists by improving efficacy, tolerability and patient compliance with once-weekly, once-monthly and even continuous six-month or full-year options. In addition, a new generation of dual receptor agonists are in development that offer hope for increased therapeutic benefits compared to marketed GLP-1 receptor agonists.

 

There are numerous recombinant proteins in various phases of clinical development as shown in Figure 1. Several candidates are currently pending approval as shown in Table 1.

 

Pending Approval

There are currently three peptide drug candidates pending approval for the treatment of type 2 diabetes as shown in Table 1. Intarcia Therapeutics has developed ITCA650, a six-month treatment that consists of a matchstick size device that utilizes the company’s Medici Drug Delivery SystemTM to provide continuous subcutaneous delivery of exenatide. In September 2017, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for ITCA650 and provided guidance regarding the manufacturing aspects in the CRL. Intarcia announced that the company does not foresee the need for a new pivotal trial or any long lead-time Chemistry, Manufacturing and Controls (CMC) activities to satisfy the FDA (2). Another late stage candidate awaiting approval is NN9535. Novo Nordisk has filed for regulatory approval with the FDA, the European Medicines Agency (EMA) and the Japanese Ministry of Health, Labour and Welfare for NN9535 (semaglutide), a once-weekly GLP-1 receptor agonist for patients with type 2 diabetes (3). In China, Uni-Bio Science is developing Uni-E4 (recombinant exenatide). The company has completed a Phase III clinical trial of Uni-E4 for the treatment of type 2 diabetes and the product is pending approval in China (4).

Table 1: Type 2 Diabetes Peptide Drug Candidates Pending Approval (4)

Product Name Active Ingredient Condition Treated Highest Phase Companies
ITCA650 exenatide Non-Insulin-Dependent Diabetes Mellitus(PA) Pending Approval Intarcia Therapeutics Inc, Les Laboratoires Servier
NN9535 semaglutide Non-Insulin-Dependent Diabetes Mellitus(PA), Obesity(I) Pending Approval Novo Nordisk A/S
Uni-E4 exenatide (recombinant) Non-Insulin-Dependent Diabetes Mellitus(PA), Insulin-Dependent Diabetes Mellitus(PC) Pending Approval Uni-Bio Science Group Ltd, Luqa Pharmaceuticals

Phase III Candidates

There are two candidates currently in Phase III development for type 2 diabetes as shown as Table 2. Novo Nordisk’s once-daily long-acting oral semaglutide, NN9924, is currently in Phase III trials for type 2 diabetes. The company expects that results from their Phase IIIa program, consisting of ten studies, will be available in 2018 (3). Jiangsu Hengrui Medicine is developing PEX168, a novel GLP-1 analog that consists of pegylated loxenatide. In 2014, the company initiated two Phase III studies. One study is evaluating PEX168 combined with Metformin in the treatment of type 2 diabetes and the second study is evaluating PEX168 monotherapy in the treatment of type 2 diabetes (4).

Table 2: Type 2 Diabetes Peptide Drug Candidates in Phase III Clinical Development (4)

Product Name Active Ingredient Condition Treated Highest Phase Companies
NN9924 semaglutide Non-Insulin-Dependent Diabetes Mellitus(III) Phase III Novo Nordisk A/S, Emisphere Technologies Inc
PEX168 loxenatide (pegylated) Non-Insulin-Dependent Diabetes Mellitus(III) Phase III Jiangsu Hengrui Medicine Co Ltd

Phase II Candidates

There are many peptide therapeutics in Phase II development for diabetes as shown in Table 3. Four candidates are GLP-1 receptor agonists and three candidates are novel dual agonists. For example, Eli Lilly is developing LY3298176, a hypoglycemic dual agonist of the gastric inhibitory polypeptide receptor (GIP) and GLP-1 receptor. In addition, MedImmune has a dual agonist, MEDI0382, in development for the treatment of type 2 diabetes and obesity. MEDI0382 acts as a GLP-1 and glucagon dual agonist. Similarly, Transition Therapeutics is developing TT401 for the treatment of type 2 diabetes and obesity. TT401 is a hypoglycemic oxyntomodulin peptide, which is a dual agonist of the GLP-1 (Glucagon-Like Peptide-1) receptor and glucagon receptors (4)

Table 3: Type 2 Diabetes Peptide Drug Candidates in Phase II Clinical Development (4)

Product Name Active Ingredient Condition Treated Highest Phase Companies
Exenatide 4P THERAPEUTICS exenatide Non-Insulin-Dependent Diabetes Mellitus(II) Phase II 4P Therapeutics
HM11260C efpeglenatide Non-Insulin-Dependent Diabetes Mellitus(II), Obesity(II) Phase II Hanmi Pharmaceutical Co Ltd, Sanofi
LY3298176 -- Non-Insulin-Dependent Diabetes Mellitus(II) Phase II Eli Lilly and Company
MEDI0382 -- Non-Insulin-Dependent Diabetes Mellitus(II), Obesity(II) Phase II MedImmune, AstraZeneca
NN9828 interleukin 21 monoclonal antibody (recombinant, human), liraglutide Insulin-Dependent Diabetes Mellitus(II) Phase II Novo Nordisk A/S
PT302 exenatide Non-Insulin-Dependent Diabetes Mellitus(II) Phase II Peptron Inc, Yuhan Corporation
TT401 oxyntomodulin Non-Insulin-Dependent Diabetes Mellitus(II), Obesity(II) Phase II Eli Lilly and Company, Transition Therapeutics Inc, Opko Health Inc

Phase I Candidates

The early phase pipeline of peptides for type 2 diabetes is robust with fourteen known candidates as listed in Table 4. Notably, several GLP-1 receptor agonists are in Phase I development and further dual agonists are on the horizon such as BI456906, TT402 and ZP2929. Also, there are Phase I candidates in the pipeline with different mechanisms of action such as Boehringer Ingelheim’s BI473494, a long-acting amylin receptor agonist that improves glycemic control by decreasing postprandial and fasting blood glucose levels and terminal Hb1Ac levels. Additionally, CureDM is developing Pancreate, a human proislet peptide that acts by stimulating the growth of new insulin producing islets in the pancreas. In China, Shenzhen HighTide Biopharmaceutical is developing HTD4010, an analog of islet neogenesis-associated protein (INGAP) peptide (4).

Table 4: Type 2 Diabetes Peptide Candidates in Phase I Clinical Development (4)

Product Name Active Ingredient Condition Treated Highest Phase Companies
AZP531 -- Prader-Willi Syndrome(II), Non-Insulin-Dependent Diabetes Mellitus(I), Ischemia(PC) Phase II Alize Pharma, Eli Lilly and Company Limited
BI456906 -- Non-Insulin-Dependent Diabetes Mellitus(I), Obesity(I) Phase I Zealand Pharma A/S, Boehringer Ingelheim Pharma GmbH & Co KG, Boehringer Ingelheim International GmbH
BI473494 -- Non-Insulin-Dependent Diabetes Mellitus(I), Obesity(I) Phase I Boehringer Ingelheim International GmbH, Zealand Pharma A/S
DA3091 exenatide (pegylated) Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Dong-A Socio Holdings
Exenatide MERCK exenatide Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Merck & Co Inc
FT228 exenatide Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Flamel Technologies SA, Avadel Pharmaceuticals Plc
HS20004 -- Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Jiangsu Hansoh Pharmaceutical Group Co Ltd
HTD4010 -- Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Shenzhen HighTide Biopharmaceutical Ltd
NB1001 exenatide Non-Insulin-Dependent Diabetes Mellitus(I), Short Bowel Syndrome(I), Metabolic Disorders(PC) Phase I Amunix Operating Inc, Naia Pharmaceuticals Inc, Diartis Pharmaceuticals Inc, Versartis Inc
ORMD0901 exenatide Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Oramed Pharmaceuticals
Pancreate human proislet peptide Non-Insulin-Dependent Diabetes Mellitus(I), Insulin-Dependent Diabetes Mellitus(PC) Phase I CureDM Group Holdings LLC, Sanofi
Recombinant Exendin-4 CSPC PHARMA exenatide (recombinant) Non-Insulin-Dependent Diabetes Mellitus(I) Phase I China Shijiazhuang Pharmaceutical Group Co Ltd
TT402 glucagon like peptide 1 Non-Insulin-Dependent Diabetes Mellitus(I) Phase I Eli Lilly and Company, Transition Therapeutics Inc
ZP2929 -- Non-Insulin-Dependent Diabetes Mellitus(I), Obesity(I) Phase I Zealand Pharma A/S, Boehringer Ingelheim International GmbH

Conclusion

The type 2 diabetes space is competitive but long-acting treatments and oral formulations offer the promise of new options to help physicians tailor treatments for patients based on their personal criteria. Efficacy, tolerability, cost and convenience may also vary among candidates in the pipeline offering additional advantages or disadvantages for patients. To support companies and organizations working in the area of diabetes, Bachem offers a wide array of catalog research peptides, custom peptide synthesis, production of peptide-based new chemical entities and generic active pharmaceuticals ingredients.

 

References

(1) A. Garber, Long-Acting Glucagon-Like Peptide 1 Receptor Agonists, Diabetes Care. 34(Supplement 2), S279-S284 (2011)

(2) Intarcia Provides Corporate Update, Intarcia Therapeutics (2017)

(3) R&D Pipeline, Novo Nordisk (2017)

(4) Medtrack (2017)

MEET BACHEM: VERENA HUBER, GROUP LEADER RELATIONSHIP MARKETING

PT: What is your official job title at Bachem?

Verena: Group Leader Relationship Marketing

 

PT: How long have you been with Bachem? Where did you work before Bachem?

Verena: I have started my journey with Bachem in March 2017. Previously, I managed a cluster focusing on plastic injection molding.

 

PT: Briefly, what do you do at Bachem?

Verena: I look into processes and professionalization of trade shows, events, marketing collateral and I am also increasingly getting involved in e-marketing.

 

PT: What is your academic background/degrees or training?
Verena: I obtained a bachelor degree in Business, specializing in hospitality and tourism and a master degree in Business, focusing on entrepreneurship with two majors in innovation and growth management.

 

PT: What do you like to do outside of work (interests, hobbies)?

Verena: Over the last 3 years I have become an avid diver. So the deep blue is my passion. Besides, I also enjoy hiking in summer and skiing in winter.

 

PT: What is your business motto?

Verena: The only thing constant is change. Embrace it.

 

PT: What do you like most about your job?

Verena: Pioneering means making a difference. Therefore we constantly have to come up with fresh ideas and do what we do with excellence. Striving for excellence in a challenge environment and with a growing company like Bachem requires you to stay on your toes!

 

PT: Do you like to communicate any key message to the reader?

Verena: Do what you love. Love what you do.

 

PT: Thank you very much Verena.

PEPTIDE HIGHLIGHTS

LITERATURE CITATIONS

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

A. Connolly et al.

Isolation of peptides from a novel brewers spent grain protein isolate with potential to modulate glycaemic response.

International Journal of Food Science & Technology 52, 146-153 (2017)

 

J. Koffert et al.

Effects of meal and incretins in the regulation of splanchnic blood flow.

Endocr. Connect. 6, 179-187 (2017)

 

D.M. Lim et al.

Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response.

Exp. Ther. Med. 13, 2558-2564 (2017)

 

B. Yusta et al.

Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway.

Mol. Metab. 6, 503-511 (2017)