Enhancement of incretin signalling and promotion of pancreatic islet cell health by soluble protein hydrolysate

Abstract

The present disclosure relates to isolated oligopeptides capable of activating glucagon-like peptide (GLP) receptors, as well as formulations of the oligopeptides. The formulations are suitable for improving glycemic control and reducing excess body weight of overweight individuals.

Description

[0001] Docket No.: 19773-20011.40 ENHANCEMENT OF INCRETIN SIGNALLING AND PROMOTION OF PANCREATIC ISLET CELL HEALTH BY SOLUBLE PROTEIN HYDROLYSATE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 708,658, filed October 17, 2024, the content of which is hereby incorporated by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The content of the electronic sequence listing (197732001140seqlist.xml; Size: 1,461,116 bytes; and Date of Creation: October 14, 2025) is herein incorporated by reference in its entirety. FIELD The present disclosure relates to isolated oligopeptides capable of activating glucagon-like peptide (GLP) receptors, as well as formulations of the oligopeptides. The formulations are suitable for improving glycemic control and reducing excess body weight of overweight individuals. BACKGROUND Diet, exercise and sleep are central to the maintenance of good health [1]. However, consistently attaining these three pillars of health is difficult in the context of modern life-styles. Time pressures and financial constraints can necessitate shortcuts in terms of dietary choices, such as the selection of calorie-dense (and highly palatable) processed foods. This, coupled with limited opportunities for physical activity, has contributed to a significant increase in obesity rates over the past few decades, with 38% of the world’s population now classified as overweight or obese [2]. The health consequences of excess weight can be devastating with significantly increased rates of diabetes, cardiovascular disease and cancer, all a consequence of chronic inflammation and oxidative stress damage to the body. Tackling obesity will require preventative strategies including targeting the progressive weight gain that commonly occurs with ageing 1 MF-363235028 Docket No.: 19773-20011.40 [3,4]. Ageing is associated with a gradual increase in inflammation and oxidative stress within the body. This multifactorial process is influenced by factors such as a sedentary lifestyle, weight gain and an accumulation of senescent cells [5]. This not only places the individual at an increased risk of conditions such as diabetes, but also an accelerated loss of lean body mass and the development of frailty (sarcopenia) [6,7]. With an ageing population, strategies for weight management become ever more urgent to help improve overall health and quality of life [1,8]. Until quite recently, noninvasive weight management strategies were limited to reducing calorie intake and increasing levels of exercise. However, long term adherence to such approaches is challenging and ultimately the biological drive to eat is very difficult to oppose chronically [9]. Frustratingly, pharmacologic approaches were either ineffective or associated with unacceptable risk [10,11]. Fortunately, the emergence of GLP-1-based therapies such as semaglutide has transformed weight management. These therapies enable obese subjects to frequently lose 15% or more of their body weight and have demonstrated major health benefits, including a reduced risk of heart attack, stroke and renal dysfunction

[0012] . However, for individuals who are overweight, and otherwise healthy, interventions to support effective weight management remain sparse. In addition, alternatives to semaglutide, which have a reduced risk of side effects are desirable. BRIEF SUMMARY The present disclosure relates to isolated oligopeptides capable of activating glucagon-like peptide (GLP) receptors, as well as formulations of the oligopeptides. The formulations are suitable for improving glycemic control and reducing excess body weight of overweight individuals. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows normalized mean glucagon-like peptide-1 (GLP-1) receptor activity, measured by change in intracellular cyclic adenosine monophosphate (cAMP) levels, following incubation with non-fractionated soluble protein hydrolysate (SPH) derived from Atlantic salmon (Salmo salar) or GLP-1. Data points represent the mean ± standard deviation for each test condition, with experiments performed in triplicate. * indicates a p-value of >0.05 and ** indicates a p-value of <0.01 compared to PBS control. 2 MF-363235028 Docket No.: 19773-20011.40 FIG.2 shows normalized mean GLP-1 receptor activity, measured by change in intracellular cAMP levels, following incubation with non-fractionated SPH, different fractions of SPH, semaglutide or tirzepatide. Data points represent the mean ± standard deviation for each test condition, with experiments performed in triplicate. * Indicates a p-value of >0.05 and ** indicates a p-value of <0.01 compared to PBS control. FIG.3 shows normalized mean glucose-dependent insulinotropic polypeptide (GIP) receptor activity, measured by change in intracellular cAMP levels, following incubation with non-fractionated SPH or GIP. Data points represent the mean ± standard deviation for each test condition, with experiments performed in triplicate. GIP agonist dose of 1μM is equivalent to 0.004mg / mL. * Indicates a p-value of <0.05 and ** indicates a p-value of <0.01 compared to PBS negative control. FIG.4 shows normalized mean GIP receptor activity, measured by change in intracellular cAMP levels, following incubation with non-fractionated SPH, different fractions of SPH, semaglutide or tirzepatide. Data points represent the mean ± standard deviation for each test article with each experiment performed in triplicate. ** Indicates a p-value of <0.01 compared to PBS negative control. FIG.5 shows the effect of increasing concentrations of SPH on proliferation of pancreatic islet cells (ABC-TC4286 hPIC cells) from 24 to 102 hours, as compared to control (whey protein hydrolysate at 1 μL / well). FIG.6 shows the effect of various marine protein hydrolysates and bovine collagen peptides on the proliferation of pancreatic islet cells (ABC-TC4286 hPIC cells) from 24 to 102 hours compared to control (whey protein hydrolysate), with all samples dosed at 10 μL / well. VPCP are commercially available bovine collagen peptides; CPH is cod protein hydrolysate; HPH is herring protein hydrolysate; SPH-C is a salmon protein hydrolysate made with Coralase 7089. 3 MF-363235028 Docket No.: 19773-20011.40 DETAILED DESCRIPTION The present disclosure relates to isolated oligopeptides capable of activating glucagon-like peptide (GLP) receptors, as well as formulations of the oligopeptides. The formulations are suitable for improving glycemic control and reducing excess body weight of overweight individuals. Marine proteins are well recognized as a source of bioactive peptides (BPs)

[0013] . These are typically small peptide fragments, of less than 40 amino acids in length, and act as biological regulators that enhance health. The reported health benefits of marine BPs are diverse and therefore, individual marine protein hydrolysates can display an array of bioactivities

[0014] . These include anti-hypertensive, antioxidant and glucoregulatory actions

[0015] . While inhibition of dipeptidyl peptidase IV (DPP-IV or DPP4) has been demonstrated with several marine- derived BPs, to date, direct GLP-1 agonism has not been shown. DPP-IV inhibition slows the breakdown of GLP-1 (glucagon-like peptide), although this is a relatively weak mode of action. GLP-1 agonists show considerably greater improvements in the regulation of blood glucose levels and can enable significant weight loss. In contrast, DPP-IV inhibitors provide only moderate reductions in blood glucose and are merely weight neutral

[0016] . SPH, a soluble protein hydrolysate, contains a mixture of bioactive peptides derived through enzymatic hydrolysis of Norwegian Atlantic salmon (Salmo salar). Clinical and preclinical studies with SPH have consistently shown antioxidant and anti-inflammatory effects, improved metabolic profiles and enhanced levels of energy and vitality [17-19]. These benefits stem from the upregulation of antioxidant protective gene systems, including FTH1 (ferritin heavy chain-1) and HMOX1 (hemoxygenase-1), as well as the downregulation of the pro- inflammatory ALOX12 (12-lipoxygenase) gene system by SPH. The downstream health effects include optimized levels of ferritin and hemoglobin and a 6% to 7% reduction in body weight in overweight individuals [19,20]. In addition to reductions in body mass, increases in serum bile acid (+63%), adiponectin (+11%) and lipoprotein lipase (+15%) have also been observed along with reductions in fasting plasma glucose (FPG) (-6%) and the pro-inflammatory cytokine, IL-6 (-15%) [19,20]. However, fractions of SPH and bioactive peptides present in SPH, which are responsible for weight reduction, lowered FPG and increased adiponectin levels have not 4 MF-363235028 Docket No.: 19773-20011.40 heretofore been identified. The study described in the examples provides results from an examination of the in vitro effects of a soluble protein hydrolysate (SPH) derived from Atlantic salmon (Salmo salar) on incretin receptor activity and pancreatic islet cell protection. SPH demonstrated a dose-dependent enhancement of GLP-1 and GIP receptor activity, with significant increases of 2.4-fold (p < 0.05) and 2.6-fold (p < 0.01) at 10 mg / mL, respectively compared to control. Pancreatic islet cell assays showed a substantial proliferation effect, with up to a 57% increase at 50 μL / well, indicating potential protective properties against inflammation- induced cell loss. Notably, the smallest SPH fraction (<1000 Da) exhibited GLP-1 agonist activity comparable to semaglutide, underscoring SPH’s potential efficacy in modulating metabolic pathways. These results indicate that SPH and bioactive peptides therefrom not only enhance key incretin signalling but also promote islet cell health. As such, bioactive peptides present in the low molecular weight (MW) fraction of SPH are a promising dietary intervention to improve age-related metabolic health including countering the weight gain and underlying adverse metabolic changes that frequently occur during and after menopause Although the smallest SPH fraction, referred to in the examples and figures as “peptides <1000 Da”, some of the peptides in this fraction have a larger mass spectra. As such, the low MW fraction referred to as “peptides <1000 Da” fraction is more accurately termed as “peptides <2,500 Da”. The amino acid sequences and mass spectra of peptides <2,500 Da are shown in Table 2-1. Definitions As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural references unless the context indicates otherwise. For example, “an excipient” includes one or more excipients. It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and / or “consisting essentially of” aspects and embodiments. The term “about” as used herein in reference to a value describes from 90% to 110% of that value. For instance, about a body mass index (BMI) of 30 includes a BMI of from 27 to 33. 5 MF-363235028 Docket No.: 19773-20011.40 As used herein, the terms “glucagon-like peptide 1 receptor” and “GLP-1R” refer to a G-protein coupled receptor for GLP-1. The amino acid sequence of human GLP-1R is set forth as UniProt P43220, while the amino acid sequence of human GLP-1 is set forth as residues 98-128 of human pro-glucagon (GCG) of UniProt P01275. The terms “glucagon-like peptide 2 receptor” and “GLP-2R”, as used herein, refer to a G-protein coupled receptor for GLP-2. The amino acid sequence of human GLP-2R is set forth as UniProt O95838, while the amino acid sequence of human GLP-2 is set forth as residues 146-178 of human pro-glucagon (GCG) of UniProt P01275. As used herein, the terms “gastric inhibitory polypeptide receptor,” “glucose- dependent insulinotropic polypeptide receptor” and “GIPR” refers to a G-protein coupled receptor for GIP. The amino acid sequence of human GIPR is set forth as UniProt P48546. The terms “glucose-dependent insulintropic polypeptide,” “gastric inhibitory polypeptide” and “GIP” refer to a peptide hormone of the secretin family, which stimulates insulin secretion, and weakly inhibits gastric acid secretion. The amino acid sequence of human GIP is set forth as residues 52-93 of UniProt P09681. The term “isolated” as used herein in reference to molecules (e.g., oligopeptides), refers to molecules that are removed or otherwise purified from their natural or synthetic environment. Substantially “isolated” molecules are at least 75% free, preferably at least 90% free, more preferably at least 95%, 96%, 97%, 98% or 99% free from other components. For instance, an “isolated oligopeptide consisting of the amino acid sequence of SEQ ID NO:1” is at least at least 75% free of peptides and proteins that do not comprise the amino acid sequence of SEQ ID NO:1. The term “increasing,” and grammatical equivalents as used herein in reference to levels of G-protein coupled receptor activity, refers to causing G-protein coupled receptor activity to become greater in amount, such as measured by cellular assays. Preferably, an increase in G-protein coupled receptor activity encompasses a statistically significant increase, preferably an increase from about 1.5 to about 150 fold, from about 1.5 to about 15 fold, from about 1.5 to about 3 fold, preferably an increase of at least 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.0, 3.1, 3.2, 3.3, 3.4 or 3.5 fold. 6 MF-363235028 Docket No.: 19773-20011.40 As used herein, the terms “treating” and “treatment” refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. As such, the terms “treating” and “treatment” as used herein, do not require complete alleviation of signs or symptoms, do not require a cure, and specifically include protocols that have a modest effect on the individual. An “effective amount” of an agent disclosed herein (e.g., isolated oligopeptide or formulation thereof) is an amount sufficient to carry out a specifically stated purpose. An “effective amount” may be determined empirically in relation to the stated purpose. An “effective amount” or an “amount sufficient” of an agent is that amount adequate to affect a desired biological effect, such as a beneficial result, including a beneficial clinical result. The term “therapeutically effective amount” refers to an amount of an agent (e.g., isolated oligopeptide or formulation thereof) effective to “treat” a disease or disorder in a subject (e.g., a mammal such as a human). An “effective amount” or an “amount sufficient” of an agent may be administered in one or more doses. The terms “individual” and “subject” refer to mammals. “Mammals” include, but are not limited to, humans, non-human primates (e.g., monkeys), farm animals, sport animals, rodents (e.g., mice and rats) and pets (e.g., dogs and cats). I. Isolated Oligopeptides The isolated oligopeptides of the present disclosure comprising the amino acid sequence of any one of SEQ ID NOS: 1-1675 (set forth in Table 2-1), wherein the oligopeptide is no more than 50, 45, 40, 35 or 30 amino acids in length, optionally wherein the oligopeptide is no more than 30 amino acids in length. In some embodiments, the isolated oligopeptide comprises an amino acid sequence having at least 90% (e.g., at least 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity to any one of SEQ ID NOS:SEQ ID NOS: 1-1675. In some embodiments, the isolated oligopeptide is from 6 to 37 amino acids in length. In some embodiments, the oligopeptide is no less than 6, 7, 8, 9, 10, 11, 7 MF-363235028 Docket No.: 19773-20011.40 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 residues in length, and / or the oligopeptide is no more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8 or 7 residues in length, in which the lower limit is less than the upper limit. In some embodiments, the isolated oligopeptides of the present disclosure do not comprise a dipeptidyl peptidase-4 (DPP4) motif, wherein the DPP4 motif is X1X2X3 in which X1 is any amino acid, X2is proline or alanine, and X3is any amino acid except proline. In some embodiments, the DPP4 motif is LPG, GPL, or GPA. In some embodiments, the oligopeptide comprises the amino acid sequence of any one of SEQ ID NOS: 1-105, 107, 108, 110-199, 201- 244, 246-328, 330-349, 351-371, 373-403, 406-520, 522-533, 535-622, 624-645, 647-672, 674- 791, 793, 795-871, 873-942, 944, 945, 947-957, 959-964, 966, 968-979, 981-1004, 1006-1022, 1024-1052, 1054-1115, 1117-1139, 1141-1243, 1245-1304, 1306-1344, 1346-1358, 1360-1376, 1378-1434, 1436-1504, 1506-1614, 1616-1619, 1621-1662, and 1664-1675, wherein the oligopeptide is no more than 50, 45, 40, 35 or 30 amino acids in length, optionally wherein the oligopeptide is no more than 30 amino acids in length. In preferred embodiments, the isolated oligopeptides are capable of capable of activating human glucagon-like peptide-1 (GLP-1) receptor, preferably capable of increasing GLP-1R activity as measured in a cellular assay by at least 1.5 fold. In some embodiments, the isolated oligopeptides are further capable of activating human glucose-dependent insulinotropic polypeptide (GIP) receptor and / or human glucagon-like peptide-2 (GLP-2) receptor. In some embodiments, the oligopeptides are capable of supporting pancreatic islet cell proliferation, preferably capable of increasing viable pancreatic cell counts and / or proliferation rate by at least 25%. In some preferred embodiments, the oligopeptide is produced synthetically. In exemplary embodiments, the oligopeptide is produced by solid phase synthesis and purified by high performance liquid chromatography as known in the art. Even so, the present disclosure also provides an isolated nucleic acid encoding the oligopeptide. The nucleic acid may be present in an expression cassette or vector in operable combination with a promoter. Also provided are host cells comprising the isolated nucleic acid, expression cassette or expression vector, for recombinant expression of the oligopeptide. 8 MF-363235028 Docket No.: 19773-20011.40 II. Formulations The present disclosure provides formulations comprising at least one isolated oligopeptide of the preceding section, and at least one pharmaceutically acceptable excipient and / or an oral delivery agent. In some embodiments, the formulations may further comprise an enteric coating, liposomes, microspheres, or micro- / nano-particles. For instance, in some embodiments, the isolated oligopeptide is encapsulated within an enteric coating, liposomes, microspheres, or micro- / nano-particles. However, as the oligopeptide of the formulation is isolated, the formulations of the present disclosure do not encompass fish protein hydrolysates, such as a salmon protein hydrolysate. The amount of an oligopeptide of the disclosure, which will be effective in the treatment of a particular disorder or condition disclosed herein depends on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. In some embodiments, the dose of the oligopeptide of the present disclosure is from about 0.1 mg / kg to about 1000 mg / kg, about 1.0 mg / kg to about 100 mg / kg, or about 10 mg / kg body weight of the subject to be treated. In some embodiments, the dose of oligopeptide is no less than 0.1, 0.5, 1.0, 5.0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 500 mg / kg, and / or the dose of the oligopeptide is no more than 1000, 500, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5.0, 1.0, or 0.5 mg / kg, in which the lower limit is less than the upper limit. A. Excipients Pharmaceutically acceptable excipients of the present disclosure include, for instance, solvents, bulking agents, buffering agents, tonicity adjusting agents, and preservatives (Pramanick et al., Pharma Times, 45:65-77, 2013). In some embodiments the formulations may comprise an excipient that functions as one or more of a solvent, a bulking agent, a buffering agent, and a tonicity adjusting agent (e.g., sodium chloride in saline may serve as both an aqueous vehicle and a tonicity adjusting agent). In some embodiments, the formulations comprise an aqueous vehicle as a solvent. Suitable vehicles include for instance sterile water, saline solution, phosphate buffered saline, and Ringer’s solution. In some embodiments, the formulation is isotonic. 9 MF-363235028 Docket No.: 19773-20011.40 The formulations may comprise a buffering agent. Buffering agents control pH to inhibit degradation of the active agent during processing, storage and optionally reconstitution. Suitable buffers include for instance salts comprising acetate, citrate, phosphate or sulfate. Other suitable buffers include for instance amino acids such as arginine, glycine, histidine, and lysine. The buffering agent may further comprise hydrochloric acid or sodium hydroxide. In some embodiments, the buffering agent maintains the pH of the formulation within a range of 6 to 9. In some embodiments, the pH is greater than (lower limit) 6, 7 or 8. In some embodiments, the pH is less than (upper limit) 9, 8, or 7. That is, the pH is in the range of from about 6 to 9 in which the lower limit is less than the upper limit. The formulations may comprise a tonicity adjusting agent. Suitable tonicity adjusting agents include for instance dextrose, glycerol, sodium chloride, glycerin and mannitol. The formulations may comprise a bulking agent. Bulking agents are particularly useful when the pharmaceutical formulation is to be lyophilized before administration. In some embodiments, the bulking agent is a protectant that aids in the stabilization and prevention of degradation of the active agents during freeze or spray drying and / or during storage. Suitable bulking agents are sugars (mono-, di- and polysaccharides) such as sucrose, lactose, trehalose, mannitol, sorbitol, glucose and raffinose. The formulations may comprise a preservative. Suitable preservatives include for instance antioxidants and antimicrobial agents. However, in preferred embodiments, the formulation is prepared under sterile conditions and is in a single use container, and thus does not necessitate inclusion of a preservative. B. Oral Delivery Agents Oral delivery agents of the present disclosure include, for instance, absorption enhancers, fatty acids, enzyme inhibitors, polyethylene glycol, mucoadhesive polymers, and cell penetrating peptides (Dan et al., Children, 7:307, 2020). Commonly utilized routes of administration for therapeutic peptides and proteins include intravenous (IV), intraperitoneal (IP), and intramuscular (IM) injections. However, oral administration is preferred by patients and oral medications are typically less expensive to manufacture, distribute and administer. Unfortunately, development of orally available dosage 10 MF-363235028 Docket No.: 19773-20011.40 forms of therapeutic peptides and proteins have been complicated for a variety of reasons, including but not limited to poor stability in physiological conditions, short biological half-life, and low permeability through the epithelial barrier in the small intestine. Thus, in some embodiments, the formulations of the present disclosure are designed to protect the isolated oligopeptide from the proteolytic enzymes and acidic environment found in the stomach, such that their bioactivity is retained as they are absorbed into the bloodstream (see, e.g., Dan et al., Children, 7:307, 2020). III. Methods of Use The isolated oligopeptides and formulations of the present disclosure find use in methods and medicaments for activating a human incretin receptor. In some embodiments, the human incretin receptor comprises a human glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, the isolated oligopeptides mimic one or more actions of the incretin hormone GLP-1: slow gastric emptying; inhibit glucagon release; stimulate insulin secretion and thereby reduce hyperglycemia; and reduce food intake thereby reducing body weight. . In some embodiments, the isolated oligopeptides and formulations thereof of the present disclosure also find use in methods and medicaments for supporting pancreatic islet cell proliferation in a human subject in need thereof. In additional embodiments, the isolated oligopeptides and formulations thereof the present disclosure find use in methods and medicaments for improving glycemic control in a human subject in need thereof. As such, in some embodiments, the formulations are administered to human subjects with prediabetes or type 2 diabetes mellitus. In further embodiments, the isolated oligopeptides and formulations thereof of the present disclosure find use in methods and medicaments for managing weight in a human subject in need thereof. In some embodiments, the formulations are administering to obese subjects, such as subjects with a body mass index (BMI) of 30 or greater. In some embodiments, the formulations are administering to overweight subjects, such as subjects with a body mass index (BMI) of from 25 or greater to 30 or greater. In some embodiments, the formulation is administered as an adjunct to a reduced calorie diet and / or increased physical activity. 11 MF-363235028 Docket No.: 19773-20011.40 In some in vivo embodiments, the formulation comprising an isolated oligopeptide of the present disclosure is administered by mouth. For instance, the formulation may be administered enterically. In some embodiments, the formulation is administered by a buccal, a sublabial, or a sublingual route. IV. Enumerated Embodiments 1. A formulation comprising a low molecular weight fraction of soluble protein hydrolysate from Atlantic salmon, and at least one pharmaceutically acceptable excipient, wherein oligopeptides of the low molecular weight fraction have a length of from 6 to 37 amino acids and / or a spectra mass of from about 725 to about 2500 daltons. 2. An isolated oligopeptide comprising the amino acid sequence of any one of SEQ ID NOS: 1-1675, wherein the oligopeptide is no more than 50, 45, 40, 35 or 30 amino acids in length, optionally wherein the oligopeptide is no more than 30 amino acids in length. 3. The isolated oligopeptide of embodiment 2, wherein the oligopeptide does not comprise a dipeptidyl peptidase-4 (DPP4) motif , wherein the DPP4 motif is X1X2X3in which X1is any amino acid, X2is proline or alanine, and X3is any amino acid except proline. 4. The isolated oligopeptide of embodiment 3, wherein the DPP4 motif is LPG, GPL, or GPA. 5. The isolated oligopeptide of embodiment 3, wherein the oligopeptide comprises the amino acid sequence of any one of SEQ ID NOS: 1-105, 107, 108, 110-199, 201-244, 246- 328, 330-349, 351-371, 373-403, 406-520, 522-533, 535-622, 624-645, 647-672, 674-791, 793, 795-871, 873-942, 944, 945, 947-957, 959-964, 966, 968-979, 981-1004, 1006-1022, 1024-1052, 1054-1115, 1117-1139, 1141-1243, 1245-1304, 1306-1344, 1346-1358, 1360-1376, 1378-1434, 1436-1504, 1506-1614, 1616-1619, 1621-1662, and 1664-1675. 6. The isolated oligopeptide of any one of embodiments 2-5, wherein the oligopeptide is capable of activating a human glucagon-like peptide-1 (GLP-1) receptor. 7. The isolated oligopeptide of embodiment 6, further wherein the oligopeptide is capable of activating a human glucose-dependent insulinotropic polypeptide (GIP) receptor. 12 MF-363235028 Docket No.: 19773-20011.40 8. The isolated oligopeptide of embodiment 6 or embodiment 7, further wherein the oligopeptide is capable of activating a human glucagon-like peptide-2 (GLP-2) receptor. 9. The isolated oligopeptide of any one of embodiments 2-9, wherein the oligopeptide is capable of supporting pancreatic islet cell proliferation. 10. A formulation comprising the isolated oligopeptide of any one of embodiments 2- 9, and at least one pharmaceutically acceptable excipient. 11. The formulation of embodiment 1 or embodiment 10, wherein the at least one pharmaceutically acceptable excipient comprises an oral delivery agent, wherein the oral delivery agent comprises an absorption enhancer, a fatty acid, an enzyme inhibitor, polyethylene glycol, a mucoadhesive polymer, a cell penetrating peptide, or a combination thereof. 12. The formulation of embodiment 11, wherein the oral delivery agent comprising an absorption enhancer, optionally wherein the absorption enhancer comprises salcaprozate sodium (SNAC). 13. The formulation of embodiment 11, further comprising an enteric coating, liposomes, microspheres, and / or micro- / nano-particles. 14. An isolated nucleic acid encoding the oligopeptide of any one of embodiments 2- 9, or an expression vector comprising the nucleic acid in operable combination with a promoter. 15. A host cell comprising the isolated nucleic acid or the expression vector of embodiment 14. 16. A medicament comprising the formulation of any one of embodiments 1, 9, 10, 11, 12 or 13, optionally wherein the medicament is for improving glycemic control and / or treating insulin-resistance, or for treating prediabetes, or for treating type II diabetes. 17. A method for activating a human incretin receptor, comprising contacting the human incretin receptor with an effective amount of the formulation of any one of embodiments 1, 9, 10, 11, 12 or 13 to activate the human incretin receptor. 18. The method of embodiment 17, wherein the human incretin receptor comprises a human glucagon-like peptide-1 (GLP-1) receptor. 13 MF-363235028 Docket No.: 19773-20011.40 19. A method for supporting proliferation of pancreatic islet cells, comprising contacting the pancreatic islet cells with an effective amount of the formulation of any one of embodiments 1, 9, 10, 11, 12 or 13 to support proliferation of the pancreatic islet cells. 20. The method of embodiment 17 or 18, wherein the contacting is done in vivo. 21. The method of embodiment 19, wherein the contacting is done in vivo. 22. A method for improving glycemic control in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of embodiments 1, 9, 10, 11, 12 or 13 for improving glycemic control, optionally wherein the subject is a human subject. 23. The method of embodiment 22, wherein the subject has type 2 diabetes mellitus. 24. A method for managing weight in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of embodiments 1, 9, 10, 11, 12 or 13 for managing weight, optionally wherein the subject is a human subject. 25. The method of any one of embodiments 22-24, wherein the subject is overweight or obese, optionally wherein the subject has a body mass index (BMI) of about 25 or greater, or about 30 or greater. 26. The method of any one of embodiments 22-25, wherein the formulation is administered as an adjunct to a reduced calorie diet and / or increased physical activity. 27. The method of any one of embodiments 22-26, wherein the formulation is administered enterically. 28. The method of embodiment 27, wherein the formulation is administered by an oral, a buccal, a sublabial, or a sublingual rout, optionally wherein the formulation is administered by an oral route. 29. The method of any one of embodiments 22-26, wherein the formulation is administered parenterally. 30. The method of embodiment 29, wherein the formulation is administered by subcutaneous injection. 14 MF-363235028 Docket No.: 19773-20011.40 EXAMPLES Abbreviations: ACTB (beta-actin); AU (arbitrary units); CPH (cod protein hydrolysate); FTH1 (ferritin heavy chain 1); GIP-1 (glucose-dependent insulinotropic polypeptide-1); GLP (glucagon-like peptide); HPH (herring protein hydrolysate); hPIC (human pancreatic islet cells); LDH (lactate dehydrogenase); PBS (phosphate buffered saline); SPH (soluble protein hydrolysate); VPCP (bovine collagen peptides); and WPH (whey protein hydrolysate). EXAMPLE 1 Preparation of Biologically Active Soluble Protein Hydrolysate Soluble Protein Hydrolysate (SPH) was produced by enzymatic hydrolysis of salmon (Salmo salar) head and backbone post filleting as described (US 2021 / 0252099). Briefly, 1000 grams of ground head and backbone was added to 1000 ml of water and the mixture was heated to 50°C. 10 g of an endopeptidase enzyme (pepsin) was added and the mixture was stirred for 30 minutes. Then 10 g of an exopeptidase enzyme (carboxypeptidase) was added and the mixture was stirred for 15 minutes. Next 5 grams of Flavourzyme® (a blend of endo- and exo-proteases derived from Aspergillus oryzae, marketed by Novozymes A / S, Bagsvaerd, Denmark) was added and the mixture was stirred for 10 minutes. The endopeptidase and exopeptidase treated salmon protein mixture was subsequently heated to 85°C for 15 minutes to inactivate the proteases. After filtering, the hydrolysate fraction was concentrated to 30% dry matter in a conventional evaporator and spray-dried to yield salmon protein hydrolysate powder. EXAMPLE 2 In Vitro Activation of GLP-1 and GIP Receptors and Pancreatic Islet Cell Protection by Salmon-Derived Bioactive Peptides This example describes the assessment of effects of SPH on: (a) incretin receptors GLP-1 and GIP, and (b) pancreatic islet cell protection in vitro. Materials & Methods Fractionation of SPH. Five lots of SPH, each containing 1g, were dissolved in 10 mL of PBS buffer (pH 7.4) each. Dialysis was undertaken for twelves hours according to 15 MF-363235028 Docket No.: 19773-20011.40 dialysis bag sizes (with dialysis buffer of PBS, pH 7.4). A second dialysis was then undertaken using the same methodology followed by lyophilization to prepare lyophilizates of different molecular weights. SPH factions included peptides of <1,000 Da, 7,000-8,000 Da, 9,000-10,000 Da, and >10,000 Da were validated by measuring concentration and using high performance liquid chromatography (HPLC) testing. Assay to measure GLP-1 and GIP receptor activity. The activation of GLP-1 and GIP receptors in cAMPNomad-GLP1R and cAMPNo-mad-GIPR U2OS cell line was assessed using fluorescent sensors to measure the level of cyclic AMP, a second messenger whose levels increase upon GLP-1 or GIP receptor activation

[0028] . On day 1, the cAMPNomad-GLP1R U2OS cell line was thawed and on day 2 the cells were maintained in DMEM-F12 (Dulbecco’s Modified Eagle’s Medium, Sigma-Aldrich D8437) supplemented with 10% FBS (fetal bovine serum, Sigma-Aldrich F7524) at 37 °C in a humidified 5 % carbon dioxide (CO2) atmosphere. On day 3, the cells were plated at a concentration of 30,000 cells / plate in a 96-well plate and maintained in DMEM medium supplemented with 10 % FBS for 24h at 37 °C in a humidified 5% CO2 chamber. On day 4, the cells were incubated with SPH overnight, diluted in OptiMEM (Thermo-Fisher scientific 31985070). Conditions were tested in triplicate at different concentrations. On day 5, the medium was replaced with 100μL of PBS to perform the fluorescence intensity acquisition. For tFP650 detection, the filters 590 / 20nm and 665 / 8nm were used for excitation and emission, respectively. SPH was assessed against positive controls, a standard GLP-1 receptor agonist (Sigma-Aldrich H6795) and a standard GIP receptor agonist (Tocris 2257), both at a 127uyconcentration of 1μM (ca. 0.004mg / ml). Negative controls included PBS alone and sterilized water added to PBS. SPH was first diluted in sterilized water at 100mg / ml and filtered with a 0.2μm filter to avoid contamination. A dose response assay was performed at three concentrations in 1:10 serial dilutions of SPH starting with 10mg / ml, consistent with previous work undertaken to assess the activity of SPH. Antagonism assays were also conducted in triplicate using specific antagonists for the GLP-1 and GIP receptors, Avexitide / Exenedin 9-39 (MCE HYP0264) and GIP 3-42 (MCE HYP2542), respectively, along with different test compounds. 16 MF-363235028 Docket No.: 19773-20011.40 Red cAMPNomad biosensor’s fluorescence intensity was quantified in the cytoplasm of the living cells using the following approach. Nuclei were stained using Hoechst dye (0.5μg / ml) for thirty minutes and fluorescence was measured using the Cell Insight High- Content Bioimager (Thermo-Fisher) using filters of 380 / 10nm and 460 / 10nm for excitation and emission, respectively. To detect the fluorescence intensity of the red cAMPNomad biosensor, the filters used were 549 / 15nm and 640 / 30nm, respectively. Fluorescence was quantified using Cell Software (Thermo-Fisher). In FIG. 1.2. 3 and 4, results are expressed as fluorescence intensity in arbitrary units (AU) of the red cAMP No-mad biosensor. Pancreatic islet cell proliferation assay. ABC-TC4286 Human Pancreatic Islet Cells (hPIC) from Accegen Biotechnology (USA) were seeded in a 96 well plate at a cell density of 10,000 cells / well in 200 μL cRPMI-1640 growth medium / well with 10 μM Reg 1alpha protein (transfection supernatant). The cells were incubated for 102 hours at 37 °C. SPH bioactive peptides were dosed at 1 μL / well, 5 μL / well, 10 μL / well, & 50 μL / well to assess for potential dose-dependent response. As a control, whey protein hydrolysate was dosed at 10 μL / well. The proliferation response was measured every 24 hours using WST-1 (Roche) method. The OD450 value was read on a Tecan GENios FL multi-detection microplate reader, where the observed absorbance directly correlates to the number of viable cells / well. Assays were run in single replicate. SPH doses were selected to try and attain minimally effective levels and then assess for dose response. Results & Conclusions GLP-1 receptor agonism assay results for SPH. The change in GLP-1 activity with SPH and with a GLP-1 agonist could be seen clearly on fluorescence intensity images. As shown in FIG. 1, SPH demonstrated a dose-dependent response in GLP-1 receptor activity with the lowest concentration of 0.1mg / mL showing minimal activity. In contrast, the 1mg / mL and 10mg / mL doses resulted in a 2-fold and 2.4-fold increase in GLP-1 receptor activation, respectively, compared to negative control of phosphate buffered saline (PBS) and PBS with water. Further, the 10mg / mL dose of SPH resulted in a significant increase in GLP-1 receptor activity (p<0.05), and the 1mg / ml showed a near-significant trend (p=0.052). As a positive control, a GLP-1 receptor agonist (GLP1) was also tested, which showed a significant 4-fold 17 MF-363235028 Docket No.: 19773-20011.40 increase in GLP-1 receptor activity compared to negative control (p<0.01) at a concentration of 1μM. GLP-1 agonist activity in fractionated SPH. To determine which fraction of SPH was responsible for the GLP-1 agonist effect, the assay to measure GLP-1 receptor activity was performed with fractionated SPH. As shown in FIG.2, amongst the different fractions of SPH, a significant GLP-1 agonist effect was seen in the smallest peptide fraction, labeled as peptides < 1,000 Daltons. These peptides, at a dilution of 1mg / ml, showed a normalized mean increase of 1.87-fold in GLP-1 receptor activity, which reached statistical significance versus the PBS control (p<0.05), compared to a mean increase of 1.53-fold with SPH dosed at 10mg / ml (which did not reach significance versus control, p=0.058). The smallest peptide fraction also showed a similar agonist activity as the GLP-1 analog semaglutide, although the latter was at a higher significance level versus control (p<0.01). Semaglutide is marketed in the United States as OZEMPIC®, RYBELSUS® and WEGOVY® by Novo Nordisk (Denmark). Tirzepatide, a dual GLP-1 / GIP analog, showed an almost doubling in GLP-1 receptor activation compared to the low MW SPH fraction and semaglutide. Tirzepatide is marketed in the United States as MOUNJARO® and ZEPBOUND® by Eli Lilly and Company (Indianapolis, IN). The amino acid sequences of the oligopeptides present in the low molecular weight (MW), as well as their MW as determined by mass spectra analysis is shown in Table 2- 1. Although the low MW fraction was initially defined in terms of the dialysis cutoff as <1,000 Da, the MW of the oligopeptides in this fraction as determined by mass spectra ranged from about 725 daltons to about 2,500 daltons. As such, while the low MW fraction is referred to in FIG.2 and FIG.4 as “peptides <1,000 Da”, this low MW fraction is more accurately referred to as “peptides <2,500 Da”. In Table 2-1, oligopeptides having a DDPIV (DDP4) motif have been identified, and include oligopeptides with the amino acid sequence of SEQ ID NOS: 106, 109, 200, 245, 329, 350, 372, 404, 521, 534, 623, 646, 673, 792, 794, 872, 943, 946, 958, 965, 967, 980, 1005, 1023, 1053, 1116, 1140, 1244, 1305, 1345, 1359, 1377, 1435, 1505, 1615, 1620, and 1663. 18 MF-363235028 Docket No.: 19773-20011.40 Table 2-1. Oligopeptides of Low Molecular Weight Soluble Protein Hydrolysate 19 MF-363235028 Docket No.: 19773-20011.40 20 MF-363235028 Docket No.: 19773-20011.40 21 MF-363235028 Docket No.: 19773-20011.40 22 MF-363235028 Docket No.: 19773-20011.40 23 MF-363235028 Docket No.: 19773-20011.40 24 MF-363235028 Docket No.: 19773-20011.40 25 MF-363235028 Docket No.: 19773-20011.40 26 MF-363235028 Docket No.: 19773-20011.40 27 MF-363235028 Docket No.: 19773-20011.40 28 MF-363235028 Docket No.: 19773-20011.40 29 MF-363235028 Docket No.: 19773-20011.40 30 MF-363235028 Docket No.: 19773-20011.40 31 MF-363235028 Docket No.: 19773-20011.40 32 MF-363235028 Docket No.: 19773-20011.40 33 MF-363235028 Docket No.: 19773-20011.40 34 MF-363235028 Docket No.: 19773-20011.40 35 MF-363235028 Docket No.: 19773-20011.40 36 MF-363235028 Docket No.: 19773-20011.40 37 MF-363235028 Docket No.: 19773-20011.40 38 MF-363235028 Docket No.: 19773-20011.40 39 MF-363235028 Docket No.: 19773-20011.40 40 MF-363235028 Docket No.: 19773-20011.40 41 MF-363235028 Docket No.: 19773-20011.40 42 MF-363235028 Docket No.: 19773-20011.40 43 MF-363235028 Docket No.: 19773-20011.40 44 MF-363235028 Docket No.: 19773-20011.40 45 MF-363235028 Docket No.: 19773-20011.40 46 MF-363235028 Docket No.: 19773-20011.40 47 MF-363235028 Docket No.: 19773-20011.40 48 MF-363235028 Docket No.: 19773-20011.40 49 MF-363235028 Docket No.: 19773-20011.40 50 MF-363235028 Docket No.: 19773-20011.40 51 MF-363235028 Docket No.: 19773-20011.40 52 MF-363235028 Docket No.: 19773-20011.40 53 MF-363235028 Docket No.: 19773-20011.40 54 MF-363235028 Docket No.: 19773-20011.40 55 MF-363235028 Docket No.: 19773-20011.40 56 MF-363235028 Docket No.: 19773-20011.40 57 MF-363235028 Docket No.: 19773-20011.40 58 MF-363235028 Docket No.: 19773-20011.40 GIP receptor agonism assay results for SPH. The change in GIP activity with SPH and the GIP receptor agonist could be seen clearly on fluorescence imaging. As shown in FIG.3, SPH demonstrated a dose-dependent response in GIP receptor activity. However, only the highest concentration of 10mg / mL showed a clear upregulation in activity with a 2.6-fold increase in GIP receptor activation compared to the negative control (p<0.01). The GIP receptor agonist (positive control), at a concentration of 1μM, produced a 4-fold increase in GLP-1 receptor activation compared to PBS negative control. GIP agonist activity in fractionated SPH. While SPH at 10mg / mL exhibited marked GIP agonist activity, with a normalized mean increase in GIP receptor activity of 2.8- fold (p<0.01), none of the individual peptide fractions at 1mg / ml elicited similar levels of activity and all changes were non-significant (p>0.05). This suggests that the observed activity in SPH on GIP may be mediated by a peptide fraction between >1,000 Da and <7,000 Da. In comparison, semaglutide showed more than twice the level of GIP receptor activation with a normalized mean level of 2.89 (AU) with 1mg / ml compared to the maximum level of 1.17 (AU) seen with SPH peptides of <1,000 Da and of 9,000-10,000 Da. The activity of tirzepatide was again the higher with a 4.36-fold increase in GIP receptor activation. In addition, antagonism assays were also conducted using specific antagonists for the GLP-1 and GIP receptors. No antagonistic effects were observed at any of the tested SPH concentrations (0.1mg / ml, 1.0mg / ml and 10mg / ml) or with the laboratory standard GLP-1 and GIP agonists. Potential cellular toxicity was also assessed by means of cell line survival via nuclei count and high viability (>80%) was seen in all assays. Effects of SPH on pancreatic islet cell proliferation. Results of a first experiment to measure the potential of SPH to enhance islet cell proliferation are shown in FIG.5. Whey protein hydrolysate (WPH) was dosed at 1 μL with SPH dosed at 1 μL, 5 μL, 10 μL and 50 μL to assess a dose-response potential. No significant difference in islet cell proliferation was seen 59 MF-363235028 Docket No.: 19773-20011.40 between the 1 μL dose of SPH and control. However, a progressive increase in proliferation was noted with the higher doses of SPH, with peak proliferation rates of 29%, 47% and 57% observed at the 5 μL, 10 μL and 50 μL SPH doses, respectively. Results of a second islet cell proliferation assay are shown in FIG.6. Cod protein hydrolysate (CPH) and herring protein hydrolysate (HPH) were manufactured with the same enzymes employed to produce the SPH bioactive peptides. A new variant of SPH (designated SPH-C) was also included and was produced using a different endopeptidase (Corolase 7089) compared to the enzymes used for the CPH, HPH and SPH. Additionally, a commercially available bovine collagen peptide mixture (VPCP) was evaluated against the control (WPH), with all samples dosed at 10 μL / well. No significant difference was seen between the control and either the bovine-derived peptides or the cod-derived peptides. In contrast, HPH exhibited a peak proliferation increase of 42% and SPH-C a 32% increase compared to control. The equivalent dose for SPH in the initial assay showed a peak increase of 47%. The results indicate that the islet-protective bioactivity depends on both the specific mixture of peptidase enzymes used for protein hydrolysis and the protein source of the hydrolysate. In summary, the findings suggest that peptides contained within SPH activate GLP-1 and GIP receptors in cell line assays and support pancreatic islet cell health in vitro, activity consistent with other GLP-1 receptor agonists. Specifically, GLP-1 receptor activity was found to be localized within the low MW peptide fraction (<2,500 Da ), while GIP activation activity is contemplated to be localized within a mid MW peptide fraction (>2,500 Da and <7,000 Da). EXAMPLE 3 Evaluation of the Efficacy of Salmon-Derived Bioactive Peptides in Reducing Insulin Resistance This example describes the assessment of effects of peptides present in SPH on aspects of blood glucose control in in vivo. Materials & Methods Mice. Male C57BL / 6J mice (8 weeks old at baseline) are housed under standard conditions (12:12 light-dark cycle, 22±2°C) with ad libitum access to food and water. Mice are 60 MF-363235028 Docket No.: 19773-20011.40 acclimated to a high-fat diet (HFD) for about 8 weeks prior to treatment initiation to establish insulin resistance and diet-induced obesity. Study Groups. A randomized, controlled trial with parallel groups (n=10 mice per group) is initiated: Group 1: HFD + Vehicle control; Group 2: HFD + Low-dose Frac E (200 mg / kg) = 1g / day Frac E human dose; Group 3: HFD + High-dose Frac E (1000 mg / kg) = 5g / day Frac E human dose; and Group 4: Standard chow diet + Vehicle (lean control). Frac E (aqueous suspension) is administered via oral gavage once daily for 8 weeks. Vehicle control consists of the drug formulation buffer. Further pre-clinical studies are conducted on: (i) oligopeptides comprising the amino acid sequence of each of SEQ ID NOS: 1-1675 in place of Frac E; or (ii) oligopeptides comprising the amino acid sequence of each of SEQ ID NOS: 1-105, 107, 108, 110-199, 201- 244, 246-328, 330-349, 351-371, 373-403, 406-520, 522-533, 535-622, 624-645, 647-672, 674- 791, 793, 795-871, 873-942, 944, 945, 947-957, 959-964, 966, 968-979, 981-1004, 1006-1022, 1024-1052, 1054-1115, 1117-1139, 1141-1243, 1245-1304, 1306-1344, 1346-1358, 1360-1376, 1378-1434, 1436-1504, 1506-1614, 1616-1619, 1621-1662, and 1664-1675. Primary Outcome Measures: 1. Glucose Tolerance Test (GTT): Week 0, 4, and 8 (16h fast, 2g / kg glucose IP); 2. Insulin Tolerance Test (ITT): Week 2 and 6 (6h fast, 0.75U / kg insulin IP); and 3. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) calculation = [Fasting Glucose (mg / dL) x Fasting Insulin (μU / mL)] / 405: From fasting glucose and insulin at weeks 0, 4, 8. HOMA-IR values are used to categorize study subjects as having insulin sensitivity, mild insulin resistance, or moderate to severe insulin resistance. Secondary Outcome Measures: 1. Body weight and food intake (weekly); 2. Fasting lipid profile (endpoint): and 3. Histological analysis of liver and adipose tissue for any steatosis and inflammation. 61 MF-363235028 Docket No.: 19773-20011.40 Statistics. Data is analyzed using two-way ANOVA with Tukey's post-hoc test Significance set at p<0.05. Oligopeptides of Frac E selected for further development include those capable of statistically significant activation of a human GLP-1 receptor in the assay described in Example 2. Although the present disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced in light of the above teaching. 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Folia Biol.2013, 59, 116-22. 48. Boni-Schnetzler, M. and Meier, D.T. Islet cell inflammation in type 2 diabetes. Seminars in Immunopathology.2019, 41, 501-513. 49. Larsen, C.M., Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup- Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med.2007, 356, 1517– 1526. 50. Shimoda, M., Kanda, Y., Hamamoto, S., Tawaramoto, K., Hashiramoto, M., Matsuki, M. and Kaku, K. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia, 2011, 54, 1098-1108. 51. Framroze, B., Currie, C. and Hermansen, E. Development of a Natural Protein Hydrolysate Supplement Containing Peptidyl Inhibitors of Activin A and Myostatin to Alleviate Cancer Cachexia. 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Claims

Docket No.: 19773-20011.40 CLAIMS What is claimed is:

1. A formulation comprising a low molecular weight fraction of soluble protein hydrolysate from Atlantic salmon, and at least one pharmaceutically acceptable excipient, wherein oligopeptides of the low molecular weight fraction have a length of from 6 to 37 amino acids and / or a spectra mass of from about 725 to about 2500 daltons.

2. An isolated oligopeptide comprising the amino acid sequence of any one of SEQ ID NOS: 1-1675, wherein the oligopeptide is no more than 50, 45, 40, 35 or 30 amino acids in length.

3. The isolated oligopeptide of claim 2, wherein the oligopeptide does not comprise a dipeptidyl peptidase-4 (DPP4) motif , wherein the DPP4 motif is X1X2X3in which X1is any amino acid, X2 is proline or alanine, and X3 is any amino acid except proline.

4. The isolated oligopeptide of claim 3, wherein the DPP4 motif is LPG, GPL, or GPA.

5. The isolated oligopeptide of claim 3, wherein the oligopeptide comprises the amino acid sequence of any one of SEQ ID NOS: 1-105, 107, 108, 110-199, 201-244, 246-328, 330-349, 351-371, 373-403, 406-520, 522-533, 535-622, 624-645, 647-672, 674-791, 793, 795- 871, 873-942, 944, 945, 947-957, 959-964, 966, 968-979, 981-1004, 1006-1022, 1024-1052, 1054-1115, 1117-1139, 1141-1243, 1245-1304, 1306-1344, 1346-1358, 1360-1376, 1378-1434, 1436-1504, 1506-1614, 1616-1619, 1621-1662, and 1664-1675.

6. The isolated oligopeptide of claim 5, wherein the oligopeptide is capable of activating a human glucagon-like peptide-1 (GLP-1) receptor.

7. The isolated oligopeptide of claim 6, further wherein the oligopeptide is capable of activating a human glucose-dependent insulinotropic polypeptide (GIP) receptor.

8. The isolated oligopeptide of claim 7, further wherein the oligopeptide is capable of activating a human glucagon-like peptide-2 (GLP-2) receptor. 66 MF-363235028Docket No.: 19773-20011.40 9. The isolated oligopeptide of claim 5, wherein the oligopeptide is capable of supporting pancreatic islet cell proliferation.

10. A formulation comprising the isolated oligopeptide of claim 5, and at least one pharmaceutically acceptable excipient.

11. The formulation of claim 1 or claim 10, wherein the at least one pharmaceutically acceptable excipient comprises an oral delivery agent, wherein the oral delivery agent comprises an absorption enhancer, a fatty acid, an enzyme inhibitor, polyethylene glycol, a mucoadhesive polymer, a cell penetrating peptide, or a combination thereof.

12. The formulation of claim 11, wherein the oral delivery agent comprising an absorption enhancer, optionally wherein the absorption enhancer comprises salcaprozate sodium (SNAC).

13. The formulation of claim 11, further comprising an enteric coating, liposomes, microspheres, and / or micro- / nano-particles.

14. An isolated nucleic acid encoding the oligopeptide of claim 5, or an expression vector comprising the nucleic acid in operable combination with a promoter.

15. A host cell comprising the isolated nucleic acid or the expression vector of claim 14.

16. A medicament comprising the formulation of any one of claims 1, 9, 10, 11, 12 or 13, optionally wherein the medicament is for improving glycemic control and / or treating insulin- resistance.

17. A method for activating a human incretin receptor, comprising contacting the human incretin receptor with an effective amount of the formulation of any one of claims 1, 9, 10, 11, 12 or 13 to activate the human incretin receptor.

18. The method of claim 17, wherein the human incretin receptor comprises a human glucagon-like peptide-1 (GLP-1) receptor. 67 MF-363235028Docket No.: 19773-20011.40 19. A method for supporting proliferation of pancreatic islet cells, comprising contacting the pancreatic islet cells with an effective amount of the formulation of any one of claims 1, 9, 10, 11, 12 or 13 to support proliferation of the pancreatic islet cells.

20. The method of claim 17, wherein the contacting is done in vivo.

21. The method of claim 19, wherein the contacting is done in vivo.

22. A method for improving glycemic control in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of claims 1, 9, 10, 11, 12 or 13 for improving glycemic control.

23. The method of claim 22, wherein the subject has type 2 diabetes mellitus.

24. A method for managing weight in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of claims 1, 9, 10, 11, 12 or 13 for managing weight.

25. The method of claim 22, wherein the subject is overweight or obese, optionally wherein the subject has a body mass index (BMI) of about 25 or greater, or about 30 or greater.

26. The method of claim 25, wherein the formulation is administered as an adjunct to a reduced calorie diet and / or increased physical activity.

27. The method of claim 26, wherein the formulation is administered enterically.

28. The method of claim 27, wherein the formulation is administered by an oral, a buccal, a sublabial, or a sublingual rout, optionally wherein the formulation is administered by an oral route.

29. The method of claim 26, wherein the formulation is administered parenterally.

30. The method of claim 29, wherein the formulation is administered by subcutaneous injection. 68 MF-363235028

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