ZURI DOTAN (IL)
WO2018189661A2 | 2018-10-18 | |||
WO2006112737A1 | 2006-10-26 |
EP2900255B1 | 2019-01-30 | |||
US4256108A | 1981-03-17 | |||
US4160452A | 1979-07-10 | |||
US4265874A | 1981-05-05 |
WILLIAMS GEOFFREY M. ET AL: "Synthesis of the IGF-II-like hormone vesiculin using regioselective formation of disulfide bonds", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 11, no. 19, 1 January 2013 (2013-01-01), pages 3145, XP093024841, ISSN: 1477-0520, DOI: 10.1039/c3ob40322j
NAIR ABJACOB S.: "A simple practice guide for dose conversion between animals and human", J BASIC CLIN PHARMA, vol. 7, 2016, pages 27 - 31
LEIGHTON ET AL.: "A Practical Review of C-Peptide Testing in Diabetes", DIABETES THER, vol. 8, no. 3, June 2017 (2017-06-01), pages 475 - 487, XP055717509, DOI: 10.1007/s13300-017-0265-4
JORGENSEN ET AL., J. AM ASSOC. LAB. ANIMAL SCI, vol. 56, no. 1, 2017, pages 95 - 97
WHAT IS CLAIMED IS: 1. A method of treating diabetes in a subject in need of treatment, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of diabetes are reduced or eliminated in the subject. 2. The method of claim 1, wherein one or more of Peptides 1‐17 are administered in daily doses at respective first, second, third, fourth, and fifth different days. 3. The method of claim 2, wherein the first, second, third, fourth, and fifth different days occur on consecutive days. 4. The method of claim 2, further comprising administering sixth, seventh, and eighth daily doses of IGF‐2 or a variant thereof to the subject at respective sixth, seventh, and eighth different days. 5. The method of claim 2, further comprising administering sixth, seventh, eighth, ninth, and tenth daily doses of IGF‐2 or a variant thereof to the subject at respective sixth, seventh, eighth, ninth, and tenth different days, wherein the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth different days occur on consecutive days. 6. The method of claim 1, wherein the administering is repeated on at least 5 days. 7. The method of claim 1, wherein the administering is repeated least 10 days. 8. The method of claim 1, wherein the administering is repeated on at least 15 days. 9. The method of claim 1, wherein the administering is repeated on at least 20 days. 10. A pharmaceutical composition comprising one or more of Peptides 1‐17 or a variant thereof, and a pharmaceutically acceptable excipient. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises the one or more of Peptides 1‐17 or a variant thereof in an amount sufficient to lower a blood glucose level of a subject to about normal levels. 12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition can be administered to the subject at least once a day on at least 5 days. 13. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition can be administered to the subject at least once per day on at least 8 days. 14. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition can be administered to the subject at least once per day on at least 10 days. 15. A method of treating diabetes in a subject in need of treatment, the method comprising: administering a daily dose of one or more of Peptides 1‐17 or a variant thereof to the subject on each of N different days, wherein N is at least 5, and wherein both (a) N and (b) the daily dose of IGF‐2 or the variant thereof that is administered to the subject on each of the N different days are sufficiently high to (i) reduce the subject’s glucose levels to about normal levels prior to an end of the N different days, and (ii) keep the subject’s glucose levels at about normal levels for at least 10 days after the end of the N different days. 16. The method of claim 15, wherein the N different days are consecutive days. 17. A method of treating type 2 diabetes in a subject in need of treatment, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of type 2 diabetes are reduced or eliminated in the subject. 18. A method of preventing an onset of type 1 diabetes in a subject in need of treatment, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein the onset of type 1 diabetes in the subject is prevented. 19. A method of increasing insulin levels in a bloodstream of a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein levels of insulin in the bloodstream of the subject are increased. 20. The method of claim 19, wherein a concentration of insulin in the bloodstream of the subject is increased by at least 50% compared to an initial concentration of insulin in the bloodstream of the subject measured prior to administration of IGF‐2 or a variant thereof to the subject. 21. A method of increasing a number of functional beta cells in a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein the number of functional beta cells in the subject are increased. 22. A method preventing an onset of type 2 diabetes in a subject, the method comprising administering the one or more of Peptides 1‐17 or a variant thereof to the subject wherein the onset of type 2 diabetes in the subject is prevented. 23. A method of treating diabetes, preventing an onset of type 1 diabetes, increasing insulin levels in a bloodstream, or increasing a number of functional beta cells in a subject in need of treatment, the method comprising administering a fragment of IGF‐2 or a variant thereof to the subject wherein symptoms of diabetes are prevented, reduced, or eliminated in the subject, and wherein the fragment is at least 15 amino acids long. 24. The method of claim 23, wherein the fragment comprises Peptide 11, 16, 18, or 19. 25. The method of claim 23, wherein the fragment comprises Peptide 16. 26. The method of any one of claims 23 to 25, wherein the fragment is at least 20 amino acids long. 27. The method of any one of claims 23 to 25, wherein the fragment is at least 25 amino acids long. 28. The method of any one of claims 23 to 27, wherein the fragment is up to 30 amino acids long. 29. A pharmaceutical composition comprising a fragment of IGF‐2 comprising Peptide 11, 16, 18, or 19 or a variant thereof, and a pharmaceutically acceptable excipient. 30. The pharmaceutical composition of claim 29, wherein the fragment comprises Peptide 16. 31. The pharmaceutical composition of claim 29 or 30, wherein the fragment is at least 20 amino acids long. 32. The pharmaceutical composition of claim 29 or 30, wherein the fragment is at least 25 amino acids long. 33. The pharmaceutical composition of any one of claims 29 to 32, wherein the fragment is up to 30 amino acids long. 34. The pharmaceutical composition of any one of claims 23 to 33, wherein the fragment is Peptide 11, 16, 18, or 19. |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This Application claims the benefit of US Provisional Applications 63/254,738 (filed October 12, 2021), and 63/294,221 (filed December 28, 2021), each of which is incorporated herein by reference in its entirety. Patents, publications, and appendices cited herein are hereby incorporated by reference in their entirety.
SEQUENCE LISTING
[0002] This application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 9, 2023, is named 1462-0018W001.xml and is 31,510 bytes in size.
BACKGROUND
[0003] Diabetes mellitus (DM), commonly referred to as diabetes, is a major worldwide medical problem. As of 2015, an estimated 415 million people had diabetes worldwide, with type 2 DM making up about 90% of the cases. This represents 8.3% of the adult population, with equal rates in both women and men. The incidence of DM is increasing in most of the world populations.
[0004] Diabetes is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications. Acute complications can include diabetic ketoacidosis, non-ketotic hyperosmolar coma, or death. Serious long-term complications include heart disease, stroke, chronic kidney failure, foot ulcers, and damage to the eyes. Diabetes is due to, for example, the pancreas not p roducing enough insulin or to the cells of the body not responding properly to th e insulin produced. There are three main types of diabetes mellitus. Type 1 DM results from the pancreas's failure to pr oduce enough insulin. This form was previously referred to as “insulin‐depend ent diabetes mellitus” (IDDM) or “juvenile diabetes”. The cause is unknown. Type 2 DM begins with insulin resistance, a conditio n in which cells fail to respond to insulin properly. As the disease progresse s, a lack of insulin may also develop. This form was previously referred to as “non‐insu lin dependent diabetes mellitus” (NIDDM) or “adult‐onset diabetes.” The primary cause of Type 2 DM is excessive body weight, and insufficient exercise. Gestational diabetes is the third main form and occu rs when pregnant women without a previous history of diabetes develop high blood‐sugar levels. Type 1 DM can be managed with insulin injections. T ype 2 DM may be treated with medications with or without insulin. Gestational diabetes usually resolves after the birth of the baby. The use of insulin can require daily injections whic h are expensive and inconvenient for patients. In addition, the use of i nsulin can cause low blood sugar, headache, hunger, weakness, sweating, tremors, irritabi lity, trouble concentrating, rapid breathing, fast heartbeat, fainting, or seizure. Insul in therapy requires ongoing, daily therapy to be effective. SUMMARY OF THE INVENTION Aspects described herein provide compositions and meth ods of treating diabetes and related conditions using insulin‐like growth fac tor 2 (“IGF‐2”) or a variant thereof. In some instances, the treatment provides long‐term res ults, which eliminates the need for ongoing daily injections and the side effects and ex pense of daily insulin therapy. Aspects described herein provide methods of treating diabetes (and related conditions) in a subject in need of treatment by ad ministering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant there of to the subject at respective first, second, third, fourth, and fifth different days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or the variant thereof. Further aspects provide methods of treating diabetes by administering IGF‐2 or a variant thereof to a subject in need of treatment i n an amount from about 65 μg/kg of a weight of the subject to about 1626 μg per kg of the weight of the subject. Further aspects provide methods of lowering the blood level of glucose in a subject by administering IGF‐2 or a variant thereof to a subject in need of treatment in an amount from about 65 μg/kg of a weight of the sub ject to about 813 μg per kg of the weight of the subject. Further aspects provide pharmaceutical compositions com prising IGF‐2 or a variant thereof in an amount sufficient to lower the blood glucose level of a subject to about normal levels compared to a subject that does not r eceive the IGF‐2 or a variant thereof, and a pharmaceutically acceptable excipient. Aspects described herein provide methods of treating diabetes in a subject in need of treatment. The method comprises administering a daily dose of IGF‐2 or a variant thereof to the subject on each of N different days. In this aspect, N is at least 5, and both (a) N and (b) the daily dose of IGF‐2 or the variant thereof that is administered to the subject on each of the N different days, are sufficiently high to (i) reduce the subject’s glucose levels to about normal levels prior to an end of the N diffe rent days, and (ii) keep the subject’s glucose levels at about normal levels for at least 10 days after the end of the N different days. Aspects described herein provide methods of treating type 2 diabetes in a subject in need of treatment and having a weight. T he method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 244 μg of IGF‐2 or the variant thereof per kg of the weight. Aspects described herein provide methods of preventing an onset of type 1 diabetes in a subject having a weight. The method c omprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. Further aspects described herein provide methods of i ncreasing insulin levels in a bloodstream of a subject having diabetes and having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. Aspects described herein provide methods of increasing a number of functional beta cells in a subject having diabetes and having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. Yet further aspects described herein provide methods of preventing an onset of type 2 diabetes in a subject having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF 2 or a variant thereof to the subject on respective days, wherein each of the daily doses com prises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. Aspects described herein provide a first method of t reating diabetes in a subject in need of treatment, the method comprising administe ring one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of diabetes are reduced or eliminated in the subject. Aspects described herein provide pharmaceutical composi tion comprising one or more of Peptides 1‐17 or a variant thereof, and a pharmaceutically acceptable excipient. Aspects described herein provide a second method of treating diabetes in a subject in need of treatment. In this aspect, the m ethod comprises administering a daily dose of one or more of Peptides 1‐17 or a varian t thereof to the subject on each of N different days, wherein N is at least 5, and wherei n both (a) N and (b) the daily dose of IGF‐2 or the variant thereof that is administered to the subject on each of the N different days are sufficiently high to (i) reduce the subject’s gluco se levels to about normal levels prior to an end of the N different days, and (ii) keep the sub ject’s glucose levels at about normal levels for at least 10 days after the end of the N diffe rent days. Aspects described herein provide a third method of t reating type 2 diabetes in a subject in need of treatment, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of type 2 diabetes are reduced or eliminated in the subject. Aspects described herein provide a fourth method of preventing an onset of type 1 diabetes in a subject in a subject in need of t reatment, the method comprising administering one or more of Peptides 1‐17 or a v ariant thereof to the subject wherein the onset of type 1 diabetes in the subject is prevente d. Aspects described herein provide a fifth method of i ncreasing insulin levels in a bloodstream of a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein levels of insulin in the bloodstream of the subject are increased. Aspects described herein provide a sixth method of i ncreasing a number of functional beta cells in a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein the number of functional beta cells in the subject are increased. Aspects described herein provide a seventh method pre venting an onset of type 2 diabetes in a subject, the method comprising admin istering the one or more of Peptides 1‐ 17 or a variant thereof to the subject wherein the onset of type 2 diabetes in the subject is prevented. Aspects described herein provide an eighth method of treating diabetes in a subject in need of treatment, the method comprising administering a fragment of IGF‐2 or a variant thereof to the subject wherein symptoms of d iabetes are reduced or eliminated in the subject, and wherein the fragment is at least 1 5 amino acids long. Aspects described herein provide a method of treating diabetes, preventing an onset of type 1 diabetes, increasing insulin levels in a bloodstream, or increasing a number of functional beta cells in a subject in need of t reatment, the method comprising administering a fragment of IGF‐2 or a variant the reof to the subject wherein symptoms of diabetes are prevented, reduced, or eliminated in the subject, and wherein the fragment is at least 15 amino acids long, wherein the fragment comprises Peptide 11, 16, 18, or 19. Aspects described herein also provide a pharmaceutical composition comprising a fragment of IGF‐2 comprising Peptide 11, 16, 18, or 19 or a variant thereof, and a pharmaceutically acceptable excipient, wherein the fragment comprises P eptide 11, 16, 18, or 19. The fragment may optionally be at least 20 amino acids long, and optionally at most 30 amino acids long. The variants described above may have 80 % or greater, optionally 85%, 90%, or 95% or greater homology with the IGF‐2 or fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1‐4 depict the blood glucose levels in fou r mice during an experiment in which diabetes was induced with streptozotocin (STZ) and IGF‐2 was provided to the mouse at the time points indicated at a daily dose of 3, 000 μg/kg (1/1 dose); Figures 5A, 5B, 6A, and 6B depict the exemplary blo od glucose levels in four mice during experiments in which diabetes was induced with STZ and IGF‐2 was provided to the mouse at the time points indicated at a daily dose of 800 μg/kg (1/4 dose); Figures 7‐10 depict the exemplary blood glucose lev els in four mice during experiments in which diabetes was induced with STZ a t the indicated time points and IGF‐2 was provided to the mouse at the indicated time poi nts at a daily dose of 300 μg/kg (1/10 dose); Figures 11A, 11B, 12A, and 12B depict the exemplary blood glucose levels in four mice during experiments in which diabetes was induced with STZ and IGF‐2 was provided to the mouse at the time points indicated at a daily dose of 12,000 μg/kg. Figure 13 depicts the exemplary blood concentration o f IGF‐2 in a mouse over time following an intraperitoneal (IP) injection of 4 0 μg of IGF‐2 (total IGF‐2 and free IGF‐2); Figure 14 depicts the exemplary blood glucose levels over time in an experiment comparing the effects of insulin to IGF‐2; Figure 15 shows the blood glucose levels averaged ov er the four STZ‐treated mouse experiments depicted in Figures 1‐4; Figure 16 shows the exemplary short term effects of IGF‐2 on glucose levels and IGF‐2 levels following injection of IGF‐2 in STZ treated mice; Figure 17 shows the exemplary long term effects of IGF‐2 on glucose levels in STZ‐treated mice; Figure 18 shows glucose levels in four mice that di d not exhibit a permanent response to treatment with IGF‐2; Figure 19A shows the increase in insulin levels in four STZ‐treated mice four weeks after treatment with IGF‐2; Figure 19B shows the increase in c‐peptide levels in four STZ‐treated mice four weeks after treatment with IGF‐2; Figure 20 shows the results of an exemplary glucose tolerance test in STZ‐treated mice that were treated with IGF‐2; Figure 21 depicts pancreas histology results on STZ treated mice; Figure 22 (upper panels) shows the results of an im munohistochemical staining of pancreas islets for insulin positive cells in STZ ‐treated mice treated with IGF‐2 and the associated glucose response results for the permanentl y cured and non‐permanently cured mice (lower panels); Figure 23 shows the results of an exemplary experime nt on a first group of db/db mice to determine how IGF‐2 effects blood glucose levels; Figure 24 shows the results of an exemplary experime nt on a second group of db/db mice to determine how IGF‐2 effects blood gl ucose levels; Figure 25 shows the results of an exemplary experime nt on a third and fourth groups of db/db mice to determine how IGF‐2 effect s blood glucose levels; Figure 26 shows the results of an exemplary experime nt that demonstrates how long‐term treatment with IGF‐2 enhances the levels of serum insulin in db/db mice; Figure 27 provides exemplary histopathology results sh owing the number of pancreas islet cells that test positive for insulin and glucagon after treating db/db mice with IGF‐2; Figure 28 shows the results of an immunohistochemical staining of pancreas islets for insulin positive cells in db/db mice trea ted with IGF‐2; Figure 29 shows the results of an experiment to det ermine how IGF‐2 effects the onset of type 1 diabetes in NOD mice; Figure 30A shows the results of another experiment t o determine how IGF‐2 effects the onset of type 1 diabetes in NOD mice; Figure 30B shows the serum insulin levels two weeks following treatment with IGF‐2; Figure 30C shows exemplary images of islet cells fro m untreated NOD mice (control) and NOD mice 13 weeks post treatment with IGF‐2 where the islet cells are stained for glucagon and insulin; Figure 30D is a bar graph showing the number of is let cells positive for insulin in the untreated and treated NOD mice in the experiment illustrated in Figure 30C; Figure 31 illustrates the effects of various levels of IGF‐2 on cell proliferation and insulin secretion following glucose induction in vitro ; Figure 32A illustrates the viability of STZ‐treated mouse islet cells using MTT stain following treatment with IGF‐2 compared to treatment with GLP‐1; Figure 32B illustrates increased insulin secretion fro m STZ‐treated mouse islets cells following treatment IGF‐2 compared to treatmen t with GLP‐1; and Figure 33 shows how treatment with IGF‐2 changes t he insulin response to a glucose pulse in human pancreatic islet cells. Figure 34 shows results of a beta cells insulin sec retion assay with peptides 11, 16, 18, and 19. Figure 35 shows results of a proliferation assay wit h peptide 16. DESCRIPTION OF THE PREFERRED EMBODIMENTS Aspects described herein provide methods of treating diabetes (and related conditions) in a subject in need of treatment by ad ministering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant there of to the subject at respective first, second, third, fourth, and fifth different days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or the variant thereof per kg of th e weight. The term “normal levels” refers to levels at which the subject would not be considered to be in need of treatment if the glucose level was maintained (e.g., a glucose level in a human between about 60 and about 110 mg/dL). The animal experiments described herein were conducted in mice using IGF‐2 doses adapted for mice. It is expected that a human equivalent dose (HED) will be used to treat humans with IGF‐2. In this aspect, the HED doses for IGF‐2 and variants thereof were calculated in accordance with established U.S. Food a nd Drug Administration guidelines. Nair AB, Jacob S., A simple practice guide for dose conversion between animals and human, J Basic Clin Pharma 2016;7:27‐31. For example, a HED IGF‐2 dose based on a mouse IGF‐2 dose is obtained by dividing the mouse dose by 12.3 . In this aspect, a mouse IGF‐2 dose of 800 μg/kg corresponds to a 65 μg/kg dose in human s, a mouse IGF‐2 dose of 3000 μg/kg corresponds to a 244 μg/kg dose in humans, and a mouse IGF‐2 dose of 12,000 μg/kg corresponds to a 976 μg/kg dose in humans. The HED for IGF‐2 and variants thereof, as described herein, can be calculated by dividing the mouse dose by 12.3. In another aspect, the dose of IGF‐2 and variants thereof can be at least 800, 3,000, or 12,000 μg/kg in, for example, a human. As described herein, IGF‐2 and variants thereof off er a range of treatment options for maintaining “normoglycemia” (i.e., bloo d glucose levels in a normal range) in a subject having hyperglycemia, type I and II diabetes, and related autoimmune disorders. Without being bound by theory, and based on data de scribed herein, IGF‐2 increases blood serum insulin levels and the number of functional be ta pancreatic cells. Importantly, these effects can be used for short term treatment (e.g., 30 days or less) or long term treatment. In addition, the normoglycemic effect is maintained i n many cases even after treatment is stopped. In this aspect, treatment with IGF‐2 as d escribed herein can be used to treat conditions such as type II diabetes and delay or pr event the onset of conditions such as type I diabetes. In addition, treatment with IGF‐2 and variants thereof, as described herein, can be used to prevent onset of type II diabetes. For example, IGF‐2 treatment can be used in subjects at risk for diabetes or diagnosed as being prediabetic to prevent or eliminate onset of type II diabetes. The term “diabetes” includes diabetes generally, t ype I diabetes, type II diabetes, and gestational diabetes. “Conditions related to dia betes” includes abnormal insulin resistance, abnormal blood glucose level, abnormal ins ulin level, hyperinsulinemia, glycosylated hemoglobin level, metabolic syndrome, incr eased blood pressure, high blood sugar, excess body fat around the waist, or abnormal cholesterol or triglyceride levels or a combination thereof. IGF‐2 and variants can be used to treat conditions related to diabetes. The term “IGF‐2” refers to human insulin‐like growth factor 2 and variants thereof. IGF‐2 includes SEQ ID NO. 1 and variants having at least 95% homology with SEQ ID NO. 1. In some instances, the first, second, third, fourth, and fifth different days occur on different consecutive days. In some instances, sixth, seventh, and eighth daily doses of IGF‐2 or a variant thereof can be administering sixth, seventh, eighth, ninth, and tenth daily doses of IGF‐2 or a variant thereof to the subject at respective sixth , seventh, eighth, ninth, and tenth different days, wherein the first, second, third, fou rth, fifth, sixth, seventh, eighth, ninth, and tenth different days occur on consecutive days. The methods can further comprise administering sixth, seventh, eighth, ninth, and tenth daily doses of IGF‐2 or a variant there of to the subject at respective sixth, seventh, eighth, ninth, and tenth different days, whe rein the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth diffe rent days occur on consecutive days. In some instances, each of the daily doses comprises at least 163 μg of IGF‐2 or the variant thereof per kg of the weight of the su bject. In some instances, each of the daily doses comprises at least 244 μg of IGF‐2 or the variant thereof per kg of the weight of the subject. In some instances, each of the daily doses comprises at least 813 μg of IGF‐2 or the variant thereof per kg of the weight of the subject . In some instances, each of the daily doses comprises 163‐1626 μg of IGF‐2 or the var iant thereof per kg of the weight of the subject. Further aspects provide methods of treating diabetes by administering IGF‐2 or a variant thereof to a subject in need of treatment i n an amount from about 65 μg/kg of a weight of the subject to about 1626 μg per kg of the weight of the subject. In some instances, the administering is repeated on at least 5 days. In some instances, the administering is repeated on at least 10 days. In some instances, the administering in a human can be repeated more freque ntly that in an animal, such as a mouse. In some instances, a subject can receive a d aily dose of IGF‐2 or the variant thereof divided among one, two, three, or more injections (o r another route of administration) in order to achieve a particular daily dose (e.g., at least 800 (HED of 65), 3000 (HED of 244) (referred to in the Figures as 1X1 or X1), 12,000 (HED of 976) (referred to in the Figures as 1X4 or X4) µg per kg of weight of the subject). The subject can receive a daily dose of IGF‐2 or the variant thereof on consecutive days (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, or at least 50 consecutive days). The IGF‐2 or the variant thereof can be provided to a subject by any suitable route of administration (orally, injection, subcutaneously, transdermal, etc.). Further aspects provide methods of lowering the blood level of glucose in a subject by administering IGF‐2 or a variant thereof to a subject in need of treatment in an amount from about 65 μg/kg of a weight of the sub ject to about 813 μg per kg of the weight of the subject. In some instances, the blood level of glucose is lo wered to about normal levels compared to a subject that does not receive the IGF ‐2 or a variant thereof. In some instances, the administering is repeated on at least 5 days. In some instances, the administering is repeated on at least 10 days. In some instances, the administering is repeated on at least 15 days. In s ome instances, the administering is repeated on at least 20 days. Further aspects provide pharmaceutical compositions com prising IGF‐2 or a variant thereof in an amount sufficient to lower the blood glucose level of a subject to about normal levels compared to a subject that does not r eceive the IGF‐2 or a variant thereof, and a pharmaceutically acceptable excipient. In some instances, the amount of IGF‐2 or a varia nt thereof is from about 3.25 mg to about 49 mg. In some instances, the amount o f IGF‐2 or variant thereof is from about 8.13 mg to about 41 mg. In some instances, the amo unt of IGF‐2 or variant thereof is from about 24 mg to about 33 mg. In some instances, the pharmaceutical composition is administered to a subject who exhibits abnormal insulin resistance, abnormal blo od glucose level, abnormal insulin level, abnormal glycosylated hemoglobin level, or a c ombination thereof. In some instances, the IGF‐2 is human IGF‐2 or a variant thereof. Optionally, the human IGF‐2 is recombinant. In some instances, the pharmaceutical composition can be administered to the subject at least once a day on at least 5 days. I n some instances, the pharmaceutical composition can be administered to the subject at le ast once per day on at least 8 days. In some instances, the pharmaceutical composition can be administered to the subject at least once per day on at least 10 days. In an aspect, IGF‐2 can be used in a composition to treat a patient in need thereof, wherein the patient has diabetes or type 2 diabetes in accordance with the compositions and methods described herein. Aspects described herein provide methods of treating type 2 diabetes in a subject in need of treatment and having a weight. T he method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 244 μg of IGF‐2 or the variant thereof per kg of the weight. In some instances, each of the daily doses comprises at least 976 μg of IGF‐2 or the variant thereof per kg of the weight. In some instances, the subject is treated with IGF‐2 or a variant thereof for at least a 35 day course of treatment and a concentration of glucose in a bloodstream of the subject measured after a 14 hour fast does not exceed 200 mg/dl measured after the 35 day course of treatment and a fter the 14 hour fast. Aspects described herein provide methods of preventing an onset of type 1 diabetes in a subject having a weight. The method c omprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. In some instances, each of the daily doses comprises at least 976 μg of IGF‐2 or a variant thereof per kg of the weight. In these inst ances, the concentration of glucose in the blood of the subject is less than 300 mg/dl within at least 180 minutes after the subject receives a glucose dose of 2 grams per kg of weigh t of the subject measured after the fifth daily dose and the at least 180 minutes. Further aspects described herein provide methods of i ncreasing insulin levels in a bloodstream of a subject having diabetes and having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. In some instances, a concentration of insulin in the bloodstream of the subject is increased by at least 50% compared to an initial co ncentration of insulin in the bloodstream of the subject measured prior to administration of I GF‐2 or a variant thereof to the subject. In some instances, each of the daily doses comprises at least 244 μg of IGF‐2 or the variant thereof per kg of the weight. In some instances, each of the daily doses comprises at least 976 μg of IGF‐2 or the varian t thereof per kg of the weight. Aspects described herein provide methods of increasing a number of functional beta cells in a subject having diabetes and having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF‐2 or a variant thereof to the subject on respective days, wherein each of the daily doses comprises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. In some instances, the number of functional beta cel ls in the subject is increased by at least four fold after at least 70 days of a dministering the IGF‐2 or the variant thereof to the subject compared to an initial number of functio nal beta cells in the subject measured prior to administration of IGF‐2 or a variant ther eof to the subject. In some instances, each of the daily doses comprises at least 244 μg of IGF‐2 or the variant thereof per kg of the weight. In some instances, each of the daily doses comprises at least 976 μg of IGF‐2 or the varian t thereof per kg of the weight. Yet further aspects described herein provide methods of preventing an onset of type 2 diabetes in a subject having a weight. The method comprises administering first, second, third, fourth, and fifth daily doses of IGF 2 or a variant thereof to the subject on respective days, wherein each of the daily doses com prises at least 65 μg of IGF‐2 or a variant thereof per kg of the weight. Methods and compositions described herein may further comprise reducing at least one of insulin resistance, blood glucose level, obesity, hyperinsulinemia, glycosylated hemoglobin level, or a combination thereof in the su bject. IGF‐2 includes SEQ ID NO: 1 and variants thereof including, but not limited to, human IGF‐2 and recombinant IGF‐2. The active components described for use herein can b e included in a pharmaceutically suitable vehicle, selected to render such compositions amenable to delivery by oral, rectal, parenteral (e.g., intravenou s, intramuscular, intraarterial, intraperitoneal, and the like), or inhalation routes, osmotic pump, and the like. Pharmaceutical compositions contemplated for use in th e practice of the present invention can be used in the form of a solid, a s olution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting comp osition contains one or more of the active compounds contemplated for use herein, as acti ve ingredients thereof, in admixture with an organic or inorganic carrier or excipient su itable for nasal, enteral or parenteral applications. The active ingredients may be compounded , for example, with the usual non‐ toxic, pharmaceutically and physiologically acceptable carriers for tablets, pellets, capsules, troches, lozenges, aqueous or oily suspensions, disper sible powders or granules, suppositories, solutions, emulsions, suspensions, hard or soft capsules, caplets or syrups or elixirs and any other form suitable for use. The ca rriers that can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing prep arations, in solid, semisolid, or liquid form. In addition, auxiliary, stabilizing, thickening and coloring agents may be used. The active compounds contemplated for use herein are incl uded in the pharmaceutical composition in an amount sufficient to produce the d esired effect upon the target process, condition or disease. In addition, such compositions may contain one or mo re agents selected from flavoring agents (such as peppermint, oil of wintergr een or cherry), coloring agents, preserving agents, and the like, to provide pharmaceu tically elegant and palatable preparations. Tablets containing the active ingredients in admixture with non‐toxic pharmaceutically acceptable excipients may also be man ufactured by known methods. The excipients used may be, for example, (1) inert dilue nts, such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, and the like; (2 ) granulating and disintegrating agents, such as corn starch, potato starch, alginic acid, and the like; (3) binding agents, such as gum tragacanth, corn starch, gelatin, acacia, and the like; and (4) lubricating agents, such as magnesium stearate, stearic acid, talc, and the l ike. The tablets may be uncoated, or they may be coated by known techniques to delay disintegr ation and absorption in the gastrointestinal tract, thereby providing sustained act ion over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The tablets may also be coated by the techniques de scribed in U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, each of which is incorporat ed herein by reference, to form osmotic therapeutic tablets for controlled release. When formulations for oral use are in the form of hard gelatin capsules, the active ingredients may be mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, or the like. They may als o be in the form of soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example, peanut oil, liquid paraffin, olive oil and the like. The pharmaceutical compositions may be in the form o f a sterile injectable suspension. Such a suspension may be formulated accor ding to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non‐toxic parenterally‐acceptable excipient, diluent, or solvent , for example, as a solution in 1,4‐ butanediol. Sterile, fixed oils are conventionally emp loyed as a solvent or suspending medium. For this purpose, any bland fixed oil may b e employed including synthetic mono‐ or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidan ts, and the like can be incorporated as required. In addition, sustained release systems, including semi ‐permeable polymer matrices in the form of shaped articles (e.g., films or microcapsules) can also be used for the administration of the active compound employed herein. Isolated Nucleic Acid Molecules, and Variants and Fra gments Thereof In an aspect, the disclosure provides for isolated o r recombinant nucleic acid molecules comprising nucleotide sequences encoding prot eins described herein, for example, SEQ ID NO: 1. In another aspect, the discl osure provides for isolated or recombinant nucleic acid molecules comprising nucleotid e sequences encoding proteins described herein, for example, SEQ ID NO: 1. In an aspect, proteins of the present invention are encoded by a nucleotide sequence. In an aspect, the disclosure provides for a nucleotide sequence encoding an amino acid sequence that has at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater sequence identity to a nucleotide seq uence encoding SEQ ID NO: 1. The skilled artisan will further appreciate that chan ges can be introduced by mutation of the nucleotide sequences of the invention thereby leading to changes in the amino acid sequence of the encoded proteins, without altering the biological activity of the proteins. Thus, variant isolated nucleic acid molecule s can be created by introducing one or more nucleotide substitutions, additions, or deletions into the corresponding nucleotide sequence disclosed herein, such that one or more ami no acid substitutions, additions or deletions are introduced into the encoded protein. Mu tations can be introduced by standard techniques, such as site‐directed mutagenesi s and PCR‐mediated mutagenesis. Such variant nucleotide sequences are also encompassed by the present invention. For example, conservative amino acid substitutions may be made at one or more, predicted, nonessential amino acid residues. A “nonessential” amino acid residue is a residue that can be altered from the wild‐type seq uence of a protein described herein without altering the biological activity, whereas an “essential” amino acid residue is required for biological activity. A “conservative am ino acid substitution” is one in which the amino acid residue is replaced with an amino acid r esidue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side c hains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic aci d), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyro sine, cysteine ), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta‐branched side chains ( e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Amino acid substitutions may be made in nonconserved regions that retain function. In general, such substitutions would not be made for conserved amino acid residues, or for amino acid residues residing within a conserved motif, where such residues are essential for protein activity. Examples of resid ues that are conserved and that may be essential for protein activity include, for example, residues that are identical between all proteins contained in an alignment of similar or rel ated sequences of the invention (e.g., residues that are identical in an alignment of homol ogous proteins). Examples of residues that are conserved but that may allow conservative a mino acid substitutions and still retain activity include, for example, residues that have onl y conservative substitutions between all proteins contained in an alignment of similar or rel ated sequences of the invention (e.g., residues that have only conservative substitutions bet ween all proteins contained in the alignment homologous proteins). However, one of skill in the art would understand that functional variants may have minor conserved or nonco nserved alterations in the conserved residues. Isolated Proteins, Variants, and Fragments Thereof “Variants” means proteins having an amino acid se quence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1. Variants include proteins that differ in amino acid sequence due to mutagenesis. Variant prote ins encompassed by the present invention are biologically active, that is they conti nue to possess the desired biological activity of the native protein, that is, retaining a nti diabetic activity. In various embodiments of the present invention, anti ‐diabetic proteins include amino acid sequences that are shorter than the full length sequences due to the use of an alternate downstream start site. Altered or Improved Variants It is recognized that DNA sequences of a protein ma y be altered by various methods, and that these alterations may result in DN A sequences encoding proteins with amino acid sequences different than in SEQ ID NO:1. This protein may be altered in various ways including amino acid substitutions, deletions, tr uncations, and insertions of one or more amino acids of SEQ ID NO:1, including up to 2 , 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, or more amino acid substitutions, deletions or insertions. Methods for such manipulations are generally known in the art. For ex ample, amino acid sequence variants of a protein can be prepared by mutations in the DNA. This may also be accomplished by one of several forms of mutagenesis and/or in directed e volution. The changes encoded in the amino acid sequence should not substantially affect t he function of the protein. Such variants will possess the desired anti‐diabetic acti vity. Alternatively, alterations may be made to the protein sequence of many proteins at the amino or carboxy terminus without substantiall y affecting activity. This can include insertions, deletions, or alterations introduced by mo dem molecular methods, such as PCR, including PCR amplifications that alter or extend the protein coding sequence by inclusion of amino acid encoding sequences in the oligonucleotides utilized in the PCR amplification. Alternatively, the protein sequences added can include entire protein‐coding sequences, such as those used commonly in the art to generate protein fusions. Such fusion proteins are often used to (1) increase expression of a prot ein of interest (2) introduce a binding domain, enzymatic activity, or epitope to facilitate either protein purification, protein detection, or other experimental uses known in the a rt (3) target secretion or translation of a protein to a subcellular organelle, such as the p eriplasmic space of Gram‐negative bacteria, or the endoplasmic reticulum of eukaryotic cells, the latter of which often results in glycosylation of the protein. Theory of Operation In healthy subjects, insulin regulates glucose uptake. But in diabetic subjects, insulin no longer performs that role effectively (due to either inadequate levels of insulin or insulin resistance). It has been determined that IGF 2 can be used to resolve type II diabetes. While not wishing to be bound by theory, the follow ing is one possible explanation of the mechanism of action of the disclo sed invention. The inventor theorizes that certain cells in the body, referred to herein as “BLC” (which stands for beta‐like cells) can be induced to secrete either insulin or an insu lin‐like material (“ILM”) in response to high levels of glucose. Note that while the location of the BLC within the body has not yet been identified, knowledge of their location is not necessary to obtain the results described herein. It is also possible that new BLC may be ge nerated, for example, by proliferation or transdifferentiation, or the like. More specifically, before the BLC are exposed to IGF ‐2, the BLC are dormant or inactivated, in which case they do not secrete insul in or ILM or secrete an insufficient amount of insulin or ILM. But after exposure to IGF ‐2, the BLC become activated, and will begin to secrete insulin or ILM in response to high levels of glucose. One possible mechanism of action is that exposure to IGF‐2 caus es the BLC to secrete insulin and/or ILM in response to high levels of glucose. Another possi ble mechanism of action is that the BLC are naturally programmed to secrete insulin and/or IL M in response to high levels of glucose, but an unknown substance that deactivates th e BLC is ordinarily present. Under this scenario, IGF‐2 neutralizes (e.g., switches off ) this normally prevailing deactivation substance. In either scenario, once the BLC have been activated , the BLC will sense the level of glucose in the blood, and will initiate the prod uction of insulin or ILM at levels that correspond to the level of glucose in the blood (so that higher levels of glucose will result in the production of more insulin or ILM). This product ion of insulin or ILM may occur either directly in the BLC themselves or indirectly (e.g., through the action of other cells). The insulin or ILM circulates in the blood. Another possible explanation of the mechanism of acti on is that exposure to IGF‐ 2 improves conventional beta cells’ ability to regu late the glucose levels in a subject’s body, or downregulates / turns off another mechanism that prevents the conventional beta cells from properly regulating glucose levels. To the ext ent this theory is correct, it is believed that treatment with IGF‐2 as disclosed herein may restore the normal activity of residual beta cells. EXAMPLES Example 1 – Materials and Methods C57BL/6 mice male 8–10 weeks old, housed under con ventional conditions and allowed laboratory chow and water ad libitum, were u sed in the experiments described below in Examples 3‐4. Within each experiment, anim als were matched by age and weight (20–24 g) and randomly divided into groups to rece ive different treatments. Diabetes was induced by one or more doses of streptozotocin (STZ) . Briefly, animals received intraperitoneally (i.p.) 100 mg/kg (b.w.) STZ (Cayman Chemical, Ann Arbor, MI) dissolved in citrate buffer on pH 4.5 (this procedure was repeated if needed). Clinical diabetes was defined by hypergly cemia (blood glucose levels > 300 mg/dL in fasted animals). Fasting blood glucose level s were measured three times per week and samples were taken from the tail tip after star vation for 6 hours throughout the experiment. Fasting blood glucose levels (mg/dL) were determined using the Accu‐Chek Performa glucometer (Roche Diagnostics, Mannheim, Germa ny). After approximately two weeks of stable hyperglycemia, C57BL/6 STZ mice recei ved exogenous injections of recombinant human IGF‐2 (0.3‐12mg/kg/day injection) intraperitoneally for 5‐10 consecutive days. During post‐treatment follow‐up p eriod and upon termination, mice were tested for: fasting glucose, body weight, glucose tol erance test (IPGTT), serum C‐peptide level, serum insulin level, and full blood and histo logical analysis (CBC, Chemistry, Insulin IHC and H&E). Example 2 – IGF‐2 3000 ug/kg/day Dose Figures 1‐4 show the effects of IGF‐2 at 3000 g/kg/day in four different mice treated in accordance with the description for Exampl e 1. Mouse C1 (Figure 1), Mouse C8 (Figure 2), and Mouse C6 (Figure 3) received STZ 25 days prior to beginning treatment with IGF‐2 an d exhibited a roughly four‐fold increase in fasting glucose levels. IGF‐2 (at 3000 μg/kg/da y) was administered on day 0 and ten more times within the first ten days following the initia l treatment with IGF‐2. Fasting glucose levels returned to a normal range during the ten‐d ay course of treatment with IGF‐2, and remained in the normal range until the end of the experiment. Notably, the improvement in fasting glucose levels appeared to be permanent (or at least semi‐permanent) because IGF‐2 was not administered on days 11‐82. Mouse F1 (Figure 4) was treated similarly to Mouse C1, Mouse C8 and Mouse C6 except STZ was provided 20 days prior to initial tr eatment with IGF‐2. The fasting glucose results for Mouse F1 was similar to Mouse C1, Mouse C8 and Mouse C6. While the four examples depicted in figures 1‐4 al l show long term improvement in fasting glucose levels, in some mice (not shown) the fasting glucose results returned to high levels after the 10 day course treatment with IGF‐2 ended. Example 3 – IGF‐2 ¼ Dose (800 μg/kg/day) Mouse A8 (Figure 5A) received STZ 25 days prior to beginning treatment with IGF‐2, and exhibited a roughly four‐fold increase in fasting glucose levels. IGF‐2 (at 800 μg/kg/day) was administered on day 0 and ten more times within the first ten days following the initial treatment with IGF‐2. Fasting glucose levels returned to a normal range during the ten‐day course of treatment with IGF‐2 , and remained in the normal range until the end of the experiment. The improvement in fastin g glucose levels appeared to be permanent or at semi‐permanent). Mouse A6 (Figure 5B) received STZ 25 days prior to beginning treatment with IGF‐2 and exhibited a roughly four‐fold increase in fasting glucose levels. IGF‐2 (at 800 μg/kg/day) was administered on day 0 and ten more times within the first ten days following the initial treatment with IGF‐2. Fasting glucose levels returned to a normal range during the ten‐day course of treatment with IGF‐2 , and remained in the normal range until STZ was provided again. After the second administrati on of STZ, fasting glucose levels rose back into the diabetic range, indicating that the me chanism responsible for returning the glucose levels to the normal range was susceptible t o destruction by STZ. Mice F3 and F4 (Figures 6A and 6B) received STZ 20 days prior to beginning treatment with IGF‐2 and exhibited a roughly four fold increase in fasting glucose levels. IGF‐2 (at 800 μg/kg/day) was administered on day 0 and ten more times within the first ten days following the initial treatment with IGF‐2. Fa sting glucose levels returned to a normal range during the ten‐day course of treatment with IGF‐2, but went back up to around 400 after the ten day course of injections ended. Thus, for these two mice, long‐term results were not achieved. In this example, the results at the 800 μg/kg/day dosage were variable. Half the mice had a full or almost full resolution (i.e., wi th blood glucose levels remaining in the vicinity of 200 mg/dl as in Figures 5A and 5B). Th e remaining mice had a partial improvement (i.e., with blood glucose levels remaining in the vicinity of 400 mg/dl as in Figures 6A and 6B). Example 4 – IGF 300 ug/kg/day Dose Mouse B5 (Figure 7) was treated with STZ three time s (25, 20, and 17 days) prior to an initial 300 μg/kg/day of IGF‐2 followed by ten additional 300 μg/kg/day doses of IGF‐2 the course of ten days. Unlike the higher‐dose sit uations described above in connection with Figures 1‐6, the fasting glucose levels did not re turn to a normal range, and long‐term results were not observed. Mouse B6 (Figure 8) was treated similarly to Mouse B5 except Mouse B6 received two doses of STZ at 20 and 12 days prior to the course of treatment with IGF‐2 at a 300 μg/kg/day dose. The results were similar to the results obtained for Mouse B5. Mouse B3 (Figure 9) was treated similarly to Mouse B5. Although this mouse did experience a temporary drop in fasting glucose levels from days 10‐25, the long‐term results were similar to the results for Mouse B5. Mouse B4 (Figure 10) was treated similarly to Mouse B5 except Mouse B6 received a single dose of STZ 25 days prior to the course of treatment with IGF‐2 at a 300 μg/kg/day dose. This mouse also experienced a tempor ary drop in fasting glucose levels from days 10‐25, but the long‐term results were similar to the results for Mouse B5. Example 5 – Comparison of Repetitions In some instances, the number of repetitions appears to be a factor in achieving long‐term results. Figures 11A, 11B, 12A, and 12B depict the exemplary blood glucose levels in four mice during experiments in which diabetes wa s induced with streptozotocin (STZ) and IGF‐2 was provided to the mouse at the time points indicated at a daily dose of 12,000 μg/kg. More specifically, when IGF‐2 was provided to the mice on each of 12 consecutive days, long‐term improvements in blood glucose levels were obtained (see Figures 11A and 11B). But when IGF‐2 was provided to the mice on only 5 consecutive days, long‐term improvements in blood glucose levels were not obtaine d (see Figures 12A and 12B). In one aspect, the long‐term return of blood gluco se to normal levels depends on both the number of repetitions and the IGF‐2 dosag e of each repetition. A treatment regiment can consider a combination of these two fac tors. In some instances, when either the number of repetitions or the dosage of each rep etition is too small, the glucose levels can eventually return to their elevated values. In s ome instances, when both the number of repetitions and the dosage in each repetition is lar ge enough, a long‐term return of blood glucose to normal levels is achieved (e.g., as descr ibed above in connection with Figures 1‐5 and 11). Example 6 – Pharmacokinetics of IGF‐2 (40 μg in traperitoneal injection) Figure 13 shows the level of total IGF‐2 (referred to in the figure as “Factor A”) in the blood over time following a 40 μg intraperitone al injection. The results show a peak total concentration of IGF‐2 total (about 16 μg) and 1 μg free IGF‐2, as determined by ELISA (enzyme‐linked immunosorbent assay) over a 240 minut e time frame. Without being bound by this theory, it is believed that IGF‐2 binding proteins may initially inactivate the biological activity of free IGF‐2. And over time, the bond b etween IGF‐2 and the binding protein may be released, increasing the bioavailability of IGF‐2 and leading to a longer term effective treatment. Example 7 – Blood Glucose Concentration Kinetics of IGF‐2 vs. Insulin Figure 14 shows the comparative blood glucose concent ration kinetics between insulin and IGF‐2 (referred to in the figure as Factor A”) in a glucose tolerance test in mice. Notably, after either insulin or IGF‐2 was administ ered, the glucose level decreased. IGF‐2 therefore provides an effect that mimics insulin with in the body, and that effect is referred to herein as an “insulinomimetic” effect. But not ably, as shown in Figure 14, the insulinomimetic effect of IGF‐2 endures for signific antly longer than the blood‐glucose lowering effects of insulin. More specifically, when 1 unit of insulin per kg was administered, the recovery in glucose levels began after two hours . But when 800 µg/kg of IGF‐2 was administered, the recovery in glucose levels began af ter six hours. Moreover, in the latter case, the glucose levels did not begin to rise unti l two hours after the IGF‐2 was no longer detectable in the blood (see Figure 13). In this ex ample, administering IGF‐2 can provide better results than administering insulin with respect to blood glucose levels, even when only a single dose was used. Without being bound by this theory, it is possible that the IGF‐2 combines with a number of binding proteins in the b lood and its active free form is then released slowly from the complex. Example 8 ‐ Discussion Taken together, the data in Figures 13 and 14 show that insulinomimetic effects of IGF‐2 are separate from the long‐term effects of IGF‐2 described above in connection with figures 1‐5. The insulinomimetic effect can be used for the treat ment of hyperglycemia, while the long‐term effect may serve to fully, or partially, cure diabetes long‐term. In addition, the blood glucose lowering effect of IGF‐ 2 is not diminished by presence of high “insulin resistance” typical of type 2 diabetes t reated with insulin. Unlike conventional diabetes treatment using insulin ( where the dosage must be controlled precisely to prevent hypoglycemia), a very wide range of IGF‐2 dosages can be tolerated by living subjects without causing hypoglyce mia. More specifically, in the examples above, a 10:1 ratio of dosages (i.e., betwe en 3000 µg and 300 µg) did not cause hypoglycemia. Thus, IGF‐2 compositions and methods a s described herein can advantageously be used to effectively treat hyperglyce mia without the life‐threatening risks associated with insulin therapy (e.g., hypoglycemia an d insulin resistance). In addition, IGF‐ 2, when used as described herein in connection with Figures 1‐5, can produce a long‐term effect beyond the period of treatment to reduce or even cure diabetes. Example 9 – STZ Treated Mice Figures 15‐23 show the results of experiments with mice treated with STZ. STZ eliminates or reduces the secretory capability of pan creatic β cells. STZ‐treated mice serve as models of both type 1 diabetes and late stage t ype 2 diabetes. Figure 15 shows the blood glucose levels averaged ov er the four STZ‐treated mouse experiments depicted in Figures 1‐4 before tr eatment (left panel) and after treatment (right panel) with the 3000 µg/kg/day dose of IGF‐2. As shown in Figure 15, daily intraperitoneal treatment with the 3000 µg/kg/day of IGF‐2 reduced the blood glucose level to a normal range (e.g., 100‐200 mg/dL glucose) wi thin 3‐5 days and maintained the normal level for the remainder of the 10 day window during which IGF‐2 was administered. Hypoglycemia was never observed, even when the IGF‐ 2 dose was increased to 12,000 µg/kg/day. Figure 16 shows the exemplary short term effects of IGF‐2 (referred to in the figure as “Factor A” or FA) on glucose levels a nd IGF‐2 levels over a 240 minute time course following injection of IGF‐2 in STZ‐treated mice. More specifically, the top panel illustrates the drop in glucose blood levels in three STZ‐trea ted mice after receiving a 800 µg/kg/day dose of IGF‐2 over a 240 minute time course. The bottom panel shows the rise in total IGF‐2 (upper trace) over the same time course compared to free IGF‐2 (i.e., uncomplexed IGF‐2). IGF‐2 is part of a complex system comprising IGF 1 and IGF‐2 along with binding proteins, proteases and other interacting molecules. A single 8 00 µg/kg dose of IGF‐2 injected intraperitoneally lowers hyperglycemic blood glucose le vels of 300‐500 mg/dL to a normal level (100‐200 mg/dL) for periods of over four hou rs. Normoglycemia is maintained while total serum IGF‐2 is reduced to very low levels. Free IGF‐2 levels are a small fraction of the total IGF‐2 concentration over the time course of the experiment. Without being bound by this theory, it is believed that a slow release of IGF‐2 from a serum complex can maintain normal blood glucose levels. Figure 17 shows the exemplary long term effects of IGF‐2 (referred to in the figure as FA) on glucose levels in STZ‐treated mic e. More specifically, Figure 17 shows a long term 300 day follow up study of four mice during a nd following a 10 day course of treatment with IGF‐2 at a 3000 μg/kg/day dose. Th e data shows that even though no additional doses of IGF‐2 were administered after t he initial 10 day course of treatment, normal blood glucose levels are maintained out to at least 300 days post treatment. It is believed that the four mice were permanently cured o f STZ‐induced diabetes by a single 10 day course of treatment. In contrast to the results depicted in Figure 17, F igure 18 depicts experimental results for four STZ‐treated mice who received a 1 0 day course of treatment with IGF‐2 at a 3000 μg/kg/day dose. These mice initially responded to treatment with a 3000 μg/kg/day dose of IGF‐2 but were not permanently cured. Alth ough data was not collected, it is believed that continued treatment of these mice would have maintained blood glucose levels in the normal range. Thus, mice who are not permanently cured can continue to be treated with IGF‐2 or a variant thereof in order to control their diabetes. Figure 19A shows the increase in insulin levels four weeks after treatment with IGF‐2. The treatment resulted in a significant incr ease of the insulin concentration post treatment for the permanently cured mice. More specif ically, four weeks post treatment, serum insulin was increased by 50% in the permanentl y cured mice compared to STZ treated control mice which did not receive IGF‐2 treatment. Figure 19B shows a 12‐fold increase in c‐peptide levels of four STZ‐treated mice four weeks post treatment as described in Figures 18 and 19A. C‐peptide is a biomarker used to assess pancreatic beta cell function and is normally produced in equimolar amounts to endogenous insulin. Leighton et al., A Practical Review of C‐Peptide Testing in Diabetes, Diabetes Ther. 2017 Jun; 8(3): 475–487. Figure 20 shows the results of an intraperitoneal gl ucose tolerance test on STZ‐ treated mice that were treated with IGF‐2. In this experiment, four STZ‐treated mice were treated with 12,000 µg/kg/day of IGF‐2 (four injec tions of 3000 µg/kg/day) 5 days and two mice were treated for 10 days. A glucose tolerance test was performed 50 days post‐ treatment with IGF‐2 by challenging the treated mic e with a 2 grams/kg dose of glucose and determining the blood glucose level over a 180 minut e time course. The blood glucose curves of the treated mice were compared to results for a saline control, and normal (nondiabetic) obese and normal (nondiabetic) lean mice based on published literature (Jorgensen et al., J. Am Assoc. Lab. Animal Sci 201 7 56(1): 95‐97). Five of the IGF‐2‐treated mice were permanently cured, and their responses to the glucose tolerance test fell between the glucose tolerance results from the litera ture for non‐diabetic obese mice and non‐diabetic lean mice. Mouse O1 was not permanentl y cured, and its glucose levels were higher than the normal obese mouse. Figure 21 depicts pancreas histology results on STZ treated mice. These results show that treatment using IGF‐2 results in a signi ficant increase in the number of cells that test positive for insulin in the permanently cured m ice as compared to the non‐permanently cured and the control (i.e., saline injection) mice. Permanently cured mice showed an almost four fold increase in the number of functiona l beta cells. The non‐control mice were treated once a day for 10 days with a 3000 µg/kg dose of IGF‐2. The mice were sacrificed on day 35 and pancreas cells were assessed as being in sulin positive or negative. Figure 22 (upper panels) shows the results of an im munohistochemical staining of pancreas islets for insulin positive cells in STZ ‐treated mice treated with IGF‐2 and for a naive mouse. The staining reveals that the permanentl y cured mouse had a higher level of insulin in its pancreas islets (as compared to a na ïve mouse), while the non‐permanently cured mouse had a lower level of insulin in its pa ncreas islets (as compared to a naïve mouse). This shows that treatment using IGF‐2 can result in a recovery of insulin secretion by pancreas islets. Figure 22 (lower panels) shows the glucose blood lev els for the non‐permanently cured mouse and permanently cured mouse. Mice were t reated as described for Figure 21. Example 10 – db/db Mice (Lep db ) db/db mice are bred to have a leptin deficiency, in creasing susceptibility of the mice to obesity, insulin resistance, and type 2 diab etes (T2D). Figure 23 shows how treating db/db mice with IGF‐2 effects blood glucose levels. In this experiment, one group of db/db mice was inj ected with 3000 µg/kg/day of IGF‐2 for 68 days, a second group of db/db mice was injected with 12000 µg/kg/day of IGF‐2 for 66 days, and a third group of db/db mice was injected with saline once a day for 68 days. The results show that IGF‐2 treatment using either 3000 µg/kg/day or 12000 µg/kg/day reduced blood glucose levels (14 hour fasting blood glucose levels) to a normal range even after the end of the 68 day treatment period. Figure 24 shows the results of an experiment similar to the experiment of Figure 23 in a second group of db/db mice. The results sh ow that IGF‐2 treatment using 12,000 µg/kg/day reduced blood glucose levels (14 hour fast ing blood glucose levels) to a normal range even after the end of the 68 day treatment p eriod. But in this iteration of the experiment, the blood glucose levels of the 3000 µg /kg/day group were not reduced with respect to the control. This indicates that a daily dose larger than 3000 µg/kg can be preferable, and that daily doses of at least 12,000 µg/kg can provide better results. Figure 25 shows the results of two additional experi ments in which db/db mice were treated with IGF‐2. In one experiment (left p anel), one group of db/db mice was injected with a daily dose of 12000 µg/kg of IGF 2 divided in two injections per day for 70 days, while another group of db/db mice was injected with saline. The results show that IGF‐ 2 treatment using 12000 µg/kg/day reduced blood gluc ose levels (14 hour fasting blood glucose levels) to a normal range even after the en d of the 70 day treatment period. In another experiment (right panel), one group of db/db mice was injected with a daily dose of 12000 µg/kg of IGF‐2 divided in two injections pe r day for 35 days, while another group of db/db mice was injected with saline. The results sho w that IGF‐2 treatment using 12000 µg/kg/day reduced blood glucose levels (14 hour fast ing blood glucose levels) to a normal range even after the end of the 35 day treatment p eriod. Figure 26 shows how long‐term treatment with IGF‐ 2 enhances the levels of serum insulin in db/db mice. In this experiment, one group of db/db mice (labeled FA X1) was injected with 3000 µg/kg of IGF‐2 once a day for 68 days, a second group of db/db mice (labeled FA X4) was injected with a daily dose of 12000 µg/kg of IGF‐2 divided in two injections per day for 68 days, and a third group of db/db mice was injected with saline. Serum insulin levels were measured 6.5 weeks after t he end of the 68 day treatment. Treatment with the 12,000 µg/kg daily dose increased serum insulin levels by about 50% with respect to the control. Figure 27 provides results of histopathology and immu nohistochemical studies showing the number of pancreas islet cells that test positive for insulin (left panel) and glucagon (right panel) in db/db mice. In this experi ment, one group of db/db mice was injected with 12000 µg/kg of IGF‐2 on each of 70 consecutive days, a second group of db/db mice was injected with saline, and a third group of db/db mice was a naïve control group. The mice were sacrificed for pathology 70 days after the end of the initial 70 day treatment. The results show a more than 50% increase in the n umber of insulin‐positive cells, which indicates beta cell proliferation. Evidence obtained t hus far does not support the assumption that the increase in the number of insuli n‐positive results from trans‐ differentiation of glucagon‐secreting alpha cells int o beta cells. Figure 28 shows immunohistochemical staining of pancre as islet cells from db/db mice. In this experiment, one group of db/db mice ( labeled X4) was injected with 12000 µg/kg of IGF‐2 on each of 70 consecutive days, a second group of db/db mice (labeled X1) was injected with 3000 µg/kg of IGF‐2 on each of 70 consecutive days, and a third group of db/db mice (labeled control) was injected with saline . The mice were sacrificed for pathology 70 days after the end of the initial 70 day treatment. These images show an increase in insulin positive cells in a dose‐depend ent manner. The control panels show a positive stain for insulin, which increases in intens ity in the 3000 µg/kg/day mice, and increases again in intensity in the 12,000 µg/kg/day mice. Taken together, these data show that IGF‐2 can be used to treat type 2 diabetes or prevent onset of type 2 diabetes in prediabetic subjects. Example 11 – Non‐Obese Diabetic (NOD) Mice Non‐Obese Diabetic (NOD) mice are a polygenic model for spontaneous autoimmune type 1 diabetes (T1D). NOD mice have an elevated risk for development of autoimmune type 1 diabetes. Thus, NOD mice were used to determine whether treatment IGF‐2 reduces spontaneous development of type 1 dia betes. Figure 29 shows the effects of IGF‐2 treatment on the incidence of spontaneous autoimmune attack / type 1 diabetes in NOD mice. In this experiment, one group of NOD mice (right panel) was injected with 3000 µg/kg of IGF‐2 on each of 76 consecutive days, and a second group of NOD mice (left panel) was in jected with saline. The results show that the incidence of spontaneous autoimmune attack was re duced dramatically by the IGF‐2 treatment. More specifically, at the end of the 76 days of treatment, only two of the treated mice had developed high glucose levels. Figure 30A depicts how many NOD mice have develope d autoimmune type I diabetes during an initial 66 days of treatment with IGF‐2, and at various intervals post‐ treatment. In this experiment, one group of NOD mice was injected with 3000 µg/kg of IGF‐ 2 on each of 66 consecutive days, and a second gro up of NOD mice was injected with saline. The incidence of spontaneous autoimmune type 1 diabet es was significantly reduced in the treated mice with respect to the control. Figure 30B depicts the levels of serum insulin in N OD mice measured two weeks after a 66 day course of treatment using IGF‐2. Mice that were treated with 3000 µg/kg/day of IGF‐2 had serum insulin levels that were about 4‐fold higher than the control mice. Taken together, these results show that IGF‐2 can be use d to prevent onset of type I diabetes. Figure 30C shows the results of an exemplary experim ent in which NOD mice were untreated or treated with IGF‐2. As shown in Figure 30C, untreated NOD mice showed complete destruction of islet cells due to autoimmune attack, as evidenced by the complete lack of histological staining for insulin, and the r elatively small amount of histological staining for glucagon. In contrast, NOD mice treated with IGF‐2 for 13 weeks had fully functional islet cells as indicated by significant hi stological staining for both glucagon and insulin. Figure 30D confirms the results shown in Figure 30C and provides the number of cells staining positive for insulin in NOD mice trea ted with IGF‐2 (right bar) versus untreated NOD mice (left bar). Example 12 – In Vitro Experiments in β‐MIN6 Cel ls β‐MIN6 cells serve as an in vitro model of mouse pancreatic islets. β‐MIN6 cells were used as an in vitro model to measure the effe cts of treatment with IGF‐2. Figure 31 shows the effects of IGF‐2 on cell coun t (e.g., cell proliferation) and insulin secretion at three different concentrations (5 nM, 20 nM, 80 nM) on β‐MIN6 cells compared to control, untreated β‐MIN6 cells. The left panel of Figure 31 shows that IGF‐2 incr eases cell proliferation in a dose‐ dependent manner after a 1 week treatment at the th ree measured concentrations. The right panel of Figure 31 shows that IGF‐2 also in creases insulin secretion (following glucose induction) in a dose‐dependent manner after a 1 we ek treatment. GLP‐1 (a satiety hormone) does not increase insulin secretion (right p anel). The results confirm the in vivo results discussed above and show that IGF‐2 can in crease the number of cells and insulin secretion. Figure 32A shows the effects of IGF‐2 on normal m ouse islet cell viability using an MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenylt etrazolium bromide] dye in STZ‐treated mouse islets. Yellow dye MTT is converted to a purp le dye by mitochondrial reductase in viable cells. Therefore, the amount of purple dye pr esent determined by measuring optical density of cells at 570 nm serves as a measurement of cell viability. As shown in Figure 32A, mouse islet viability increased in a dose dependent manner with increasing concentrations of IGF‐2. In contrast, GLP‐1 (a satiety hormone) did not significantly increase mouse islet viability. Figure 32B shows the effects of IGF‐2 on insulin secretion from STZ‐treated mouse islets 48 hours after treatment IGF‐2. Mouse islet cells were treated with 2.5 mM STZ and subsequently treated with either IGF‐2 (FA) at 50 nM and 500 nM, or with GLP‐1 at 100 nM and 1000 nM. As shown in Figure 32B, insulin se cretion increased in a dose dependent manner with increasing concentrations of IGF‐2. In contrast, GLP‐1 (a satiety hormone) did not significantly increase insulin secretion. Figure 33 shows the effects of IGF‐2 in vitro on human pancreatic islet cells. As shown in Figure 33, treating human pancreatic islet cells with IGF‐2 at a concentration of 50 nM for four days increased insulin secretion in resp onse to a glucose pulse by nearly 50% compared to untreated human pancreatic islet cells. Example 12a – In vitro insulin secretion and in v itro proliferation assay Transgenic C57BL/6 mouse insulinoma cell line (MIN6) cells originate from a transgenic C57BL/6 mouse insulinoma expressing an insu lin‐promoter/T‐antigen construct. MIN6 cells express GLUT‐2 and glucokinase and respo nd to glucose within the physiological range in the presence of nicotinamide (Miyazaki et a l., 1990). This in vitro screening system used MIN6 beta cells provided by AddexBio Inc. (a g lobal provider of quality products in research and development for the academia, pharmaceuti cal, and biotechnology industries), which were routinely grown as previously described (Ishihara et al., 1993). Cell Secretion Assay: To measure insulin secretion in response to active peptides, MIN6 cells were plated in 24‐well culture plates a t 6 × 105 cells/well. After 48hr, cells were washed twice and incubated in serum free medium (DME M 25 mM glucose, 2 mM l‐ glutamine, and 1 mM sodium pyruvate) for 2hr with a ctive peptides. Following incubation step induction medium was collected (stored at ‐20 °C until assayed) for insulin ELISA analysis (Mercodia Mouse Insulin ELISA #10‐1247‐01) . Results appear in Figure 34. Proliferation stimulation of novel active peptides: In this in vitro screening system Human Embryonic Kidney (HEK) 293 cells were u sed, provided by American Type Culture Collection (accession number CRL‐1573). Cell Proliferation Assay: PrestoBlue™ Cell Viability Reagent (A13262, Invitrogen, Carlsbad, CA, U SA) was utilized for cell viability. This assay was carried out in 96‐well culture plates at 1000 cells/well according to the manufacturer’s instructions. Each well contained the cells to be tested with cultured medium and active peptide/ligand, and was incubated a t 37 °C for 2 h. After incubation of 100 μL 10X PrestoBlue reagent, the absorbance was m easured at 570/600 nm using Microplate Absorbance Reader. Results appear in Figure 35. Example 13 – Management and Treatment of Diabetes with IGF‐2 As described herein, IGF‐2 and variants thereof can be used to manage or cure diabetes. Short‐term effects include lowering blood glucose in hyperglycemic subjects and supplementing insulin secretion due to lack of suffic ient functional beta cell mass. IGF‐2 and variants thereof can also be used to pr ovide at least the following long‐ term benefits: (1) lowering blood glucose levels in patients diagnosed with type 2 diabetes, (2) relieving beta cell insulin secretion stress, (3) delaying or prevent onset of type 1 diabetes, and (4) maintaining normoglycemia. Example 14 – Treatment of NOD with IGF‐2 In one exemplary experiment, NOD mice were treated w ith a 3000 µg/kg daily doses of IGF‐2 for 150 days. 4/5 of the treated mice maintained normoglycemia compared to 1/4 of the control mice. In another exemplary experiment, NOD mice were treated with a 3000 µg/kg daily dose of IGF‐2 for 75 days wi th follow‐up glucose measurements taken for an additional 90 days (during which IGF‐2 was not administered). 5/8 of the treated mice maintained normoglycemia compared to 2/11 of the cont rol mice. The average insulin secretion of the treated mice in both of these expe riments was five times greater than the control mice. Example 15 – Treatment of db/db Mice In one exemplary experiment, db/db mice were treated with a 12,000 µg/kg daily dose for 70 days with 70 days of follow up (during which IGF‐2 was not administered). All the treated mice maintained normoglycemia for at leas t 50 days following treatment. In another exemplary experiment, db/db mice were treated with a 12,000 µg/kg daily dose for 35 days with 35 days of follow up (during which IG F‐2 was not administered). All the treated mice maintained normoglycemia for 35 days following t reatment. Example 16 – Summary of Safety/Toxicity No pathologies were identified related to treatment i n blood samples, and tissue samples from thirty organs (pancreas, liver, etc.) at the end of 10 days of treatment with IGF‐2, 24 days after termination of IGF‐2 treatme nt, and 100 days after termination of 30 days of treatment with IGF‐2. Example 17 – IGF‐2 Peptides and Fragments A “fragment” of IGF‐2 is a sequential subset o f SEQ ID NO:1 that is at least 15 amino acids long and retains biological activity of IGF‐2 (e.g., anti‐diabetic activity). In the embodiments described below, a fragment of IGF‐2 is administered to a subject in need of treatment. Examples of fragments of IGF‐2 that may be administered include, but are not limited to: The above human FA native and synthetic novel peptid e sequence fragments can be represented as follows: Human IGF‐2 pre‐pro‐protein: >sp|P01344|IGF2_HUMAN Insulin‐like growth factor II OS=Homo sapiens OX=9606 GN=IGF2 PE=1 SV=1 MGIPMGKSMLVLLTFLAFASCCIAAYRPSETLCGGELVDTLQFVCGDRGFYFSRPASRVS RRSRGIVEECCFRSCDLALLETYCATPAKSERDVSTPPTVLPDNFPRYPVGKFFQYDTWK QSTQRLRRGLPALLRARRGHVLAKELEAFREAKRHRPLIALPTQDPAHGGAPPEMASNRK >sp|P01344‐2|IGF2_HUMAN Isoform 2 of Insulin‐like growth factor II OS=Homo sapiens OX=9606 GN=IGF2 MGIPMGKSMLVLLTFLAFASCCIAAYRPSETLCGGELVDTLQFVCGDRGFYFRLPGRPAS RVSRRSRGIVEECCFRSCDLALLETYCATPAKSERDVSTPPTVLPDNFPRYPVGKFFQYD TWKQSTQRLRRGLPALLRARRGHVLAKELEAFREAKRHRPLIALPTQDPAHGGAPPEMAS NRK >sp|P01344‐3|IGF2_HUMAN Isoform 3 of Insulin‐like growth factor II OS=Homo sapiens OX=9606 GN=IGF2 MVSPDPQIIVVAPETELASMQVQRTEDGVTIIQIFWVGRKGELLRRTPVSSAMQTPMGIP MGKSMLVLLTFLAFASCCIAAYRPSETLCGGELVDTLQFVCGDRGFYFSRPASRVSRRSR GIVEECCFRSCDLALLETYCATPAKSERDVSTPPTVLPDNFPRYPVGKFFQYDTWKQSTQ RLRRGLPALLRARRGHVLAKELEAFREAKRHRPLIALPTQDPAHGGAPPEMASNRK Human Mature IGF‐2 67 amino acid (aa 25‐91): AYRPSETLCGGELVDTLQFVCGDRGFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYC ATPAKSE The fragments of IGF‐2 described below were designe d and synthesized based on mass spectrometry results from post bariatric human s erum: Representative results Protein Depletion Resin following DS (differential sol ubilization) method using 7 M urea, 20 mM dithiothreitol and ice‐cold acetone/70% acetonitri le. The isolated proteins were trypsinized and analyzed by LC‐MSMS and the data w as analyzed by the Max Quant. Differential analysis was used to identify biomolecula r components (peptides) the concentration of which was elevated in post bariatric human serum specimens. PEPTIDE SEQUENCE LISTING Further examples of fragments of IGF‐2 that may be administered include the following peptides. AYRPSETLCGGELVDTLQFVCG AlaTyrArgProSerGluThrLeuCysGlyGlyGluLeuValAspThrLeuGlnPheVal CysGly Length = 22 amino acids Mw = 2359.07Da Peptide 2: DRGFYFSRPASRVSRRSR AspArgGlyPheTyrPheSerArgProAlaSerArgValSerArgArgSerArg Length = 18 amino acids Mw = 2200.57Da Peptide 3: GIVEECCFRSCDLALLETYCATPAK GlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGluThrTyrCys AlaThrProAlaLys Length = 25 amino acids Mw = 2736.31Da Peptide 4: GIVEECCFRSCDLALLETYCATPAKSE GlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGluThrTyrCys AlaThrProAlaLysSerGlu Length = 27 amino acids Mw = 2952.51Da Peptide 5: GIVEECCFRSCDLALLETYCATPAKSE Phosphorylation: {pSer}, phosphorylation at S10 GlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGluThrTyrCys AlaThrProAlaLysSerGlu Length = 27 amino acids Mw = 2952.51Da Peptide 6: GIVEECCFRSCDLALLETYCATPAKSERDVSTP GlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGluThrTyrCys AlaThrProAlaLysSerGluAr gAspValSerThrPro Length = 33 amino acids Mw = 3608.25Da Peptide 7: GFYFSRPASRVSRRSRGIVEECCFRSCDLALLETYCATPAK GlyPheTyrPheSerArgProAlaSerArgValSerArgArgSerArgGlyIleValGlu GluCysCysPheArgSerCysAspLeuAla LeuLeuGluThrTyrCysAlaThrProAlaLys Length = 41 amino acids Mw = 4647.57Da Peptide 8: GFYFSRPASRVSRRSRGIVEECCFRSCDLALLE GlyPheTyrPheSerArgProAlaSerArgValSerArgArgSerArgGlyIleValGlu GluCysCysPheArgSerCysAspLeuAla LeuLeuGlu Length = 33 amino acids Mw = 3811.57Da Peptide 9: Disulfide Bridge: 22‐27 (SS bond 22‐27) GFYFSRPASRVSRRSRGIVEECCFRSCDLALLE GlyPheTyrPheSerArgProAlaSerArgValSerArgArgSerArgGlyIleValGlu GluCysCysPheArgSerCysAspLeuAla LeuLeuGlu Length = 33 amino acids Mw = 3811.57Da Peptide 10: LQFVCGDRGFYFSRPASRPASRVSRRSRGI LeuGlnPheValCysGlyAspArgGlyPheTyrPheSerArgProAlaSerArgProAla SerArgValSerArgArgSer ArgGlyIle Length = 30 amino acids Mw = 3430.38Da Peptide 11: SRVSRRSRGIVEECCFRSCDLALLE SerArgValSerArgArgSerArgGlyIleValGluGluCysCysPheArgSerCysAsp LeuAlaLeuLeuGlu Length = 25 amino acids Mw = 2885.49Da Peptide 12: Disulfide Bridge: 14‐19 (SS bond 14‐19) SRVSRRSRGIVEECCFRSCDLALLE SerArgValSerArgArgSerArgGlyIleValGluGluCysCysPheArgSerCysAsp LeuAlaLeuLeuGlu Length = 25 amino acids Mw = 2885.49Da Peptide 13: SCDLALLETYCATPAKSERDVSTP SerCysAspLeuAlaLeuLeuGluThrTyrCysAlaThrProAlaLysSerGluArgAsp ValSerThrPro Length = 24 amino acids Mw = 2570.98Da Peptide 14: GIMEECCFRSCDLALLETYCATPAKSE GlyIleMetGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGluThrTyrCys AlaThrProAlaLysSerGlu Length = 27 amino acids Mw = 2984.58Da Peptide 15: SRVSRRSRGIVEECCFRSCDLALLETYCA SerArgValSerArgArgSerArgGlyIleValGluGluCysCysPheArgSerCysAsp LeuAlaLeuLeuGluThrTyrCysAla Length = 29 amino acids Mw = 3324Da Peptide 16: RSRGIVEECCFRSCDLALLETYCATPAKSE ArgSerArgGlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGlu ThrTyrCysAlaThrProAlaLysSerGlu Length = 30 amino acids Mw = 3351.99Da Peptide 17: GIVEECCFRSCDLALLE GlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGlu Length = 17 amino acids Mw = 1900.31Da Peptide 18: Disulfide Bridge: 9‐14 (SS bond 9‐14) RSRGIVEECCFRSCDLALLETYCATPAKSE ArgSerArgGlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGlu ThrTyrCysAlaThrProAlaLysSerGlu Length = 30 amino acids Mw = 3351.99Da Peptide 19: RSRGIVEECCFRSCDLALLE ArgSerArgGlyIleValGluGluCysCysPheArgSerCysAspLeuAlaLeuLeuGlu Length = 20 amino acids Mw = 2299.63Da The fragments described above and variants thereof ca n be used in the methods and compositions described herein. Aspects described herein provide a first method of t reating diabetes in a subject in need of treatment, the method comprising administe ring one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of diabetes are reduced or eliminated in the subject. In some instances of the first method, one or more of Peptides 1‐17 are administered in daily doses at respective first, seco nd, third, fourth, and fifth different days. In some instances of the first method, the first, s econd, third, fourth, and fifth different days occur on consecutive days. Some instances of the first method further comprise administering sixth, seventh, and eighth daily doses of IGF‐2 or a var iant thereof to the subject at respective sixth, seventh, and eighth different days. Some instances of the first method further comprise administering sixth, seventh, eighth, ninth, and tenth daily doses of IGF ‐2 or a variant thereof to the subject at respective sixth, seventh, eighth, ninth, and tenth d ifferent days, wherein the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth different days occur on consecutive days. In some instances of the first method, the administe ring is repeated on at least 5 days. In some instances of the first method, the administe ring is repeated least 10 days. In some instances of the first method, the administe ring is repeated on at least 15 days. In some instances of the first method, the administe ring is repeated on at least 20 days. Aspects described herein provide pharmaceutical composi tion comprising one or more of Peptides 1‐17 or a variant thereof, and a pharmaceutically acceptable excipient. In one aspect, the pharmaceutical composition comprise s the one or more of Peptides 1‐17 or a variant thereof in an amount s ufficient to lower a blood glucose level of a subject to about normal levels. In another aspect, the pharmaceutical composition can be administered to the subject at least once a day on at least 5 days. In a further aspect, the pharmaceutical composition c an be administered to the subject at least once per day on at least 8 days. In one aspect, the pharmaceutical composition can be administered to the subject at least once per day on at least 10 days. Aspects described herein provide a second method of treating diabetes in a subject in need of treatment. In this aspect, the m ethod comprises administering a daily dose of one or more of Peptides 1‐17 or a varian t thereof to the subject on each of N different days, wherein N is at least 5, and wherei n both (a) N and (b) the daily dose of IGF‐2 or the variant thereof that is administered to the subject on each of the N different days are sufficiently high to (i) reduce the subject’s gluco se levels to about normal levels prior to an end of the N different days, and (ii) keep the sub ject’s glucose levels at about normal levels for at least 10 days after the end of the N diffe rent days. In some instances of the second method, the N diffe rent days are consecutive days. Aspects described herein provide a third method of t reating type 2 diabetes in a subject in need of treatment, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein symptoms of type 2 diabetes are reduced or eliminated in the subject. Aspects described herein provide a fourth method of preventing an onset of type 1 diabetes in a subject in a subject in need of t reatment, the method comprising administering one or more of Peptides 1‐17 or a v ariant thereof to the subject wherein the onset of type 1 diabetes in the subject is prevente d. Aspects described herein provide a fifth method of i ncreasing insulin levels in a bloodstream of a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein levels of insulin in the bloodstream of the subject are increased. Aspects described herein provide a sixth method of i ncreasing a number of functional beta cells in a subject having diabetes, the method comprising administering one or more of Peptides 1‐17 or a variant thereof to the subject wherein the number of functional beta cells in the subject are increased. Aspects described herein provide a seventh method pre venting an onset of type 2 diabetes in a subject, the method comprising admin istering the one or more of Peptides 1‐ 17 or a variant thereof to the subject wherein the onset of type 2 diabetes in the subject is prevented. Aspects described herein provide an eighth method of treating diabetes in a subject in need of treatment, the method comprising administering a fragment of IGF‐2 or a variant thereof to the subject wherein symptoms of d iabetes are reduced or eliminated in the subject, and wherein the fragment is at least 1 5 amino acids long. In some instances of the eighth method, the fragment is at least 20 amino acids long. In some instances of the eighth method, the fragment is at least 25 amino acids long. While the present invention has been disclosed with reference to certain embodiments, numerous modifications, alterations, and c hanges to the described embodiments are possible without departing from the s phere and scope of the present invention, as defined in the appended claims. Accordi ngly, it is intended that the present invention not be limited to the described embodiments , but that it has the full scope defined by the language of the following claims, and equivalents thereof.