DIABETES PEPTIDES Peptides and Diabetes

PEPTIDES FOR DIABETES RESEARCH

In 2014, according to data from the WHO, 422 million adults (or 8.5% of the population) had diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, compared with 108 million (4.7%) in 1980. Diabe- tes mellitus can be divided into two main types, type 1 or insulin-dependent diabetes mellitus (IDDM) and type 2, or non insulin-dependent diabetes mellitus (NIDDM). The absolute lack of insulin, due to destruction of the insulin producing pancreatic β-cells, is the particular disorder in type 1 diabetes. Type 2 diabetes is mainly characterized by the inability of cells to respond to insulin. The condition affects mostly the cells of muscle and fat tissue, and results in a condition known as „insulin resistance“.

Introduction means ‘to flow through’. The adjective mel- Diabetes was already known in ancient litus, which comes from Latin and means times. The name of this disease was created ‘honey-sweet’, was added by the German by the Graeco-Roman physician Aretaeus physician Johann Peter Frank (1745-1821). of Cappadocia (approx. 80 - 130 AD) and is It was introduced in order to distinguish derived from the Greek word diabainein that diabetes mellitus, also called ‘sugar diabetes’, from diabetes insipidus, where an excessive amount of urine is produced as a result of a disturbance of the hormonal control of reabsorption of water in the kid- neys. In 1889, pancreatic secretions were EFFECTS OF shown to control blood sugar levels. How- ever, it took another 30 years until insulin DIABETES was purified from the islets of Langerhans. In the following 50 years scientists detected Over time, diabetes mellitus can lead the system-wide effects of insulin in liver, to blindness, kidney failure, and nerve muscle, and adipose tissues. In the 1970s, damage. Diabetes mellitus is also an the insulin receptor was discovered, and 10 important factor in accelerating the years later, its tyrosine kinase activity was hardening and narrowing of the arter- demonstrated. Despite this steady prog- ies (atherosclerosis), leading to stroke, ress, one of the most challenging health coronary heart diseases, and other problems of the 21st century remains the blood vessel disorders. dramatic increase in diabetes mellitus that

2 is occurring throughout the world. Today fide bridge) linked by two disulfide bridges Glucose homeostasis diabetes mellitus is one of the main causes to a B-chain of 30 amino acids. β-Cells is accomplished by of death in most developed countries. secrete insulin in response to a rising level complex physiological mechanisms. Control According to data from the International of circulating glucose. The normal fasting of blood glucose levels Diabetes Federation, more than 382 million blood glucose concentration in humans and involves insulin, gluca- people around the world suffered from dia- most mammals is 80 to 90 mg per 100 ml, gon and other peptide betes in 2013. This alarming number could associated with very low levels of insulin hormones such as reach 592 million by 2035. Further 316 secretion. After a meal, excess sugars must glucagon-like peptide million people have impaired glucose toler- be stored so that energy reserves will be 1 (GLP-1) and glucose- ance, a condition that can signal oncoming available later on. Excess glucose is sensed dependent insulinotropic polypeptide (gastric diabetes. 85 - 95 % of the diabetics have by β-cells in the pancreas, which respond inhibitory polypeptide type 2 diabetes, a chronic disease associ- by secreting insulin into the bloodstream. (GIP)). ated with insulin deficiency and insulin Insulin causes various cells in the body to resistance. Complications seen with diabe- store glucose (see Fig. 1): tes range from heart disease (2 to 4 times • Insulin stimulates skeletal muscle fibers higher occurence than in non-diabetics) to convert glucose into glycogen. It also in- to blindness, kidney disease, amputations, duces the synthesis of proteins from amino nerve damage and erectile dysfunction. acids circulating in the blood. As obesity spreads, the number of type 2 • Insulin acts on liver cells. It stimulates diabetics rises. Over 80% of diabetics are them to take up glucose from the blood obese. Consequently, the treatment of risk converting it into glycogen while inhibiting factors such as obesity, hypertension, and the production of the enzymes involved in hyperlipidemia assumes major impor- glycogenolysis. tance and must be coordinated with a good • Insulin acts on fat cells to stimulate the glycemic control for the reduction in total uptake of glucose and the synthesis of fat. mortality in type 2 diabetes mellitus. In this In each case, insulin triggers these effects monograph, we describe the pancreatic and by binding to the insulin receptor, a hetero- gastrointestinal peptide hormones that are tetramer of two extracellular α-subunits involved in the control of blood glucose, the that are bonded by disulfides to two trans- classification, and the treatment of diabe- membrane β-subunits. Insulin receptor tes mellitus. activation leads to specific phosphorylation events followed by an increase in glucose Pancreatic Peptide Hormones storage and a concomitant decrease in The islets of Langerhans contain four main hepatic glucose release. cell types: β-cells secreting insulin, α-cells C-Peptide is applied as a diagnostic tool. It secreting glucagon, δ-cells secreting is released in amounts equal to insulin, so somatostatin and γ-cells secreting pancre- the level of C-peptide in the blood indicates atic polypeptide (PP). The core of each islet how much insulin is being produced by the contains mainly the β-cells surrounded pancreas. The concentration of C-peptide is by a mantle of α-cells interspersed with measured in diabetics to differentiate be- δ-cells or γ-cells. Insulin is synthesized as a tween endogenous (produced by the body) preprohormone in the β-cells of the islets of and exogenous (injected into the body) Langerhans. Removal of its signal peptide insulin, since synthetic insulin does not during insertion into the endoplasmic retic- contain the C-peptide. Inappropriate use ulum generates proinsulin which consists of insulin in persons with a low blood sugar of 3 domains: an amino-terminal B-chain, a level results in a low C-peptide level. The carboxy-terminal A-chain and a connecting C-peptide level can also be determined in peptide known as C-peptide. Within the en- patients with type 2 diabetes showing how doplasmic reticulum proinsulin is exposed much insulin is produced by the β-cells. to several specific endopeptidases. These Abnormal high amounts of C-peptide can enzymes excise the C-peptide, thereby indicate the presence of a tumor called generating the mature form of insulin, a insulinoma which secretes insulin. small protein consisting of an A-chain of 21 β-Cells also secrete a peptide hormone amino acids (containing an internal disul- known as islet amyloid polypeptide (IAPP)

3 Peptides and Diabetes

Raises High Blood Blood Sugar Sugar

Pr om ot es in s u l in

re le a s e Glucagon

breakdo Stimulates wn of glycog en Liver

Glycogen Glucose Pancreas

St imulates formation of glycogen Insulin

e Stimulation of glucose uptake s a e from blood l e r n o g a c lu Tissue cells g s (muscle, kidney, fat) te o m ro P

Lowers Low Fig. 1. Blood Blood Sugar Sugar Opposing effects of insulin and glucagon

or amylin. This 37 amino acid peptide is Fig. 1). It counterbalances the action of in- structurally related to calcitonin and has sulin, increasing the levels of blood glucose weak calcitonin-like effects on calcium and stimulating the protein breakdown metabolism and osteoclast activity. Amylin in muscle. Glucagon is a major catabolic shows about 50% sequence identity with hormone, acting primarily on the liver. The calcitonin gene-related peptide (CGRP). It is peptide stimulates glycogenolysis (glycogen stored together with insulin in the secre- breakdown) and gluconeogenesis (syn- tory granules of β-cells and is co-secreted thesis of glucose from non-carbohydrate with insulin. Amylin’s most potent actions sources), inhibits glycogenesis (glycogen include the slowing of gastric emptying and synthesis) and glycolysis, overall increas- the suppression of postprandial glucagon ing hepatic glucose output and ketone body secretion. The hormone also reduces food formation. In people suffering from diabe- intake and inhibits the secretion of gastric tes, excess secretion of glucagon plays a acid and digestive enzymes. primary role in hyperglycemia (high blood Thus, there is therapeutic potential of IAPP glucose concentration). Glucagon is clini- agonists for the treatment of patients with cally used in the treatment of hypoglycemia absolute amylin deficiency (type 1 diabe- in unconscious patients (who can’t drink). tes) or relative amylin deficiency (type 2 Somatostatin release from the pancreas diabetes). and gut is stimulated by glucose and amino In addition, amylin is the major component acids. In diabetes, somatostatin levels are of the pancreatic amyloid deposits occur- increased in pancreas and gut, presum- ring in the pancreas of patients with type 2 ably as a consequence of insulin deficiency. diabetes. Somatostatin inhibits secretion of growth Glucagon secretion is stimulated by low, hormone, insulin and glucagon. and inhibited by high concentrations of glucose and fatty acids in the plasma (see

4 Gastrointestinal Peptide Hormones NH -terminal COOH-terminal Glucose-dependent insulinotropic poly- 2 Peptide GIP Peptide peptide (GIP) and glucagon-like peptide 1 (GLP-1) have significant effects on insulin secretion and glucose regulation. They are Post-translational released after ingestion of carbohydrate- processing and fat-rich meals and stimulate insulin secretion postprandially. Both gut hormones constitute the class of incretins and share considerable sequence homology. GIP is a GIP single 42 amino acid peptide derived from a larger 153 amino acid precursor (see Fig. 2). The peptide was originally observed to inhibit gastric acid secretion (hence it was The primary physiological responses to Fig. 2. Structure of prepro-GIP designated gastric inhibitory polypeptide). GLP-1 are glucose-dependent insulin Subsequent studies have demonstrated po- secretion, inhibition of glucagon secretion tent glucose-dependent insulin stimulatory and inhibition of gastric acid secretion and effects of GIP administration in dogs and gastric emptying. All effects of GLP-1 are rodents. GIP also regulates fat metabolism exerted by activation of the GLP-1 receptor, in adipocytes, including stimulation of lipo- a seven transmembrane spanning G- protein lipase activity, fatty acid incorpora- protein-coupled receptor (GPCR), leading to tion, and fatty acid synthesis. Unlike GLP-1, increased cAMP production and enhanced GIP does not inhibit glucagon secretion or protein kinase A (PKA) activity. gastric emptying. The peptide promotes The potential use of GLP-1 for the treatment Fig. 3. β-cell proliferation and cell survival in islet of diabetes has been considered. GLP-1 ex- Structure of preproglu- cagon: GRPP, glicentin- cell line studies. erts antidiabetogenic properties in subjects related pancreatic GLP-1 is derived from the product of the with type 2 diabetes by stimulating insulin peptide; IP, intervening proglucagon gene. This gene encodes a secretion, increasing β-cell mass, inhibit- peptides. Further pep- preproprotein (see Fig. 3) that is differen- ing glucagon secretion, delaying gastric tides derived from the tially processed dependent on the tissue in emptying, and inducing satiety, thus slowing preproprotein include which it is expressed. In pancreatic α-cells, the entry of sugar into the blood. However, glicentin which is com- prohormone convertase 2 action leads to GLP-1 is rapidly degraded by the enzyme posed of amino acids 1-69, oxyntomodulin the release of glucagon. In the gut, prohor- dipeptidyl peptidase IV (DPP IV), making it (glucagon-37) consist- mone convertase 1/3 action leads to the unattractive as a therapeutic agent. ing of amino acids release of several peptides including GLP- Successful strategies to overcome this 33-69, and the major 1. Bioactive GLP-1 consists of two forms: difficulty are the use of DPP IV-resistant proglucagon fragment GLP-1 (7-37) and GLP-1 (7-36) amide. The GLP-1 receptor agonists, such as liraglutide (MPGF) comprising latter form constitutes the majority (80%) of (NN2211, a fatty acid-linked DPP IV-resis- amino acids 72-158. the circulating GLPs. tant derivative of GLP-1) or exendin-4 (ex-

Oxyntomodulin MPGF Glicentin

GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2

Post-translational processing

GLP-1 (7-36) amide

5 Peptides and Diabetes

enatide). An alternative approach is the use insulin as seen in type 1 diabetes. This lack of inhibitors of DPP IV, such as sitagliptin, of insulin sensitivity results in higher than P32/98 (H-Ile-thiazolidide hemifumarate), normal blood glucose levels. NVP DPP 728 (N-[2-(5-Cyanopyridin-2-yl- Type 2 diabetes is not HLA-linked and no amino)ethyl]-Gly-Pro-nitrile) and the Gly- autoimmune destruction of the pancre- Pro-nitrile-derived compounds vildagliptin atic cells is observed. The development of and saxagliptin. type 2 diabetes seems to be multifacto- Exendin-4 is a peptide hormone found rial. Genetic predisposition appears to be in the saliva of the Gila monster, a lizard the strongest factor. Other risk factors are native to several Southwestern American obesity and high caloric intake. Pancre- states. Like GLP-1 exendin-4 exerts its atic α-cell mass is increased, followed by effects through the GLP-1 receptor but is an exaggerated response of glucagon to much more potent than GLP-1. Exenatide, amino acids and an impaired suppression a synthetic form of exendin-4 has been ap- of glucagon secretion by hyperglycemia. proved by the FDA as an antidiabetic drug. Increased hepatic production of glucose In contrast to most drugs that work by only with a failure of the pancreas to adapt to one mechanism, exendin-4 acts by multiple this situation and resistance to the action mechanisms, such as stimulation of insulin of insulin are characteristic features of this secretion, slowing gastric emptying, and disorder. Another important morphological inhibiting the production of glucose by the feature is the amyloid deposition in islets. liver. Furthermore, exendin-4 was shown to These deposits consist of islet amyloid suppress appetite and promote weight loss. polypeptide or amylin, that is believed, to originate in the β-cell secretory granule. Classification of Diabetes Mellitus Type 2 diabetes occurs most frequently The International Diabetes Federation dis- in adults, but is being noted increasingly tinguishes between three main types of dia- in adolescents as well. Type 2 diabetes betes mellitus. This division is based upon develops slowly and the symptoms are whether the ‘blood sugar problem‘ is caused usually less severe than in type 1. Some- by insulin deficiency or insulin resistance: times the disease is only diagnosed several Type 1 diabetes (formerly known as insulin- years after its onset, when complications dependent diabetes mellitus or juvenile- are already present. Common late micro- onset diabetes) is a β-islet cell specific, vascular complications include retinopathy, T-lymphocyte-mediated autoimmune nephropathy, and peripheral and autonomic disorder. It is characterized by a failure of neuropathies. Macrovascular complications the pancreas to produce sufficient insulin. include atherosclerotic coronary peripheral Without insulin to promote the cellular up- arterial disease. take of glucose, the blood glucose concen- Gestational diabetes may be observed in trations reach high levels. At concentrations non-diabetic women during late pregnancy. above 10 mM, renal tubular reabsorption They develop a resistance to insulin and, is saturated and glucose is passed into the subsequently, high blood glucose. This type urine. The classic symptoms are excessive of diabetes is probably caused by hormones secretion of urine, thirst, weight loss and produced by the placenta. The blood glu- tiredness. cose level has to be carefully controlled as It is known that multiple genes contribute to minimize risks for mother and child, it will to the familial clustering of this disease, the return to the normal value after birth. major histocompatibility complex (MHC) being the most important of these. The Treatment of Diabetes Mellitus MHC class 2 genotype is one of the stron- Insulin is essential for the treatment of type gest genetic factors determining disease 1 diabetes. The effects of insulin and its susceptibility. mechanism of action are described above. Type 2 diabetes (formerly named non- For clinical application, either porcine or insulin-dependent diabetes mellitus or bovine insulin was given formerly. Today, maturity-onset diabetes) is associated with human insulin (produced recombinantly) is insulin resistance rather than the lack of used. A new approach is the production of

6 orally active insulin using modifications to levels by enhancing insulin-mediated Advances in genomics, make insulin resistant to enzymatic break- suppression of hepatic glucose produc- proteomics and me- down, facilitating absorption. tion (gluconeogenesis) and by enhanc- tabolomics will help us to further understand Most of the vascular consequences of insu- ing insulin-stimulated glucose uptake by the causes of type 1 lin resistance are due to the hyperglycemia skeletal muscle. Metformin is currently the and type 2 diabetes and seen in type 2 diabetes. For this reason a most widely prescribed insulin-sensitizing might eventually lead major goal of therapeutic intervention in drug in clinical use. The major site of ac- to novel therapeutic type 2 diabetes is to reduce circulating glu- tion for metformin is the liver. Its use can approaches. cose levels. There are many pharmacologi- be contraindicated in patients with liver cal strategies to accomplish these goals: dysfunction. 1) The use of α-glucosidase inhibitors (e.g. 4) The thiazolidinediones (e.g. pioglitazone) acarbose) leads to a reduction in digestion have been proven useful in treating the and thereby minimizes the consequent hyperglycemia associated with insulin absorption of glucose into the systemic resistance in both type 2 diabetes and circulation. The reduction in glucose uptake non-diabetic conditions. These products allows the pancreatic β-cells to regulate function as agonists for the peroxisome the insulin secretion more effectively. The proliferator-activated receptor-γ (PPAR-γ). advantage of α-glucosidase inhibitors is PPARs are members of a nuclear receptor that they function locally in the intestine superfamily that has important roles in car- and have no major systemic action. Plants bohydrate and lipid metabolism. Thiazoli- are rich sources of α-glucosidase inhibitors, dinediones enhance peripheral sensitivity some of which are being evaluated for their to insulin and, to a lesser degree, decrease therapeutic potential. hepatic glucose production by binding to 2) The sulfonylureas (e.g. glibenclamide) and activating the PPAR-γ. Adverse effects are referred to as endogenous insulin se- of thiazolidine-diones include weight gain, cretagogues because they induce the pan- anemia, and abnormalities in liver and en- creatic release of insulin and thus reduce zyme levels. Resistin, an adipocyte-derived plasma glucose. Sulfonylureas function peptide, first identified during a search by binding to and inhibiting the pancre- for targets of thiazolidinediones, has been atic ATP-dependent potassium channels found to be downregulated by thiazolidin- normally involved in the glucose-mediated ediones. insulin secretion. Unwanted side-effects 5) GLP-1 analogs stimulate insulin release, of sulfonylureas are appetite stimulation, inhibit glucagon secretion, slow gastric probably via their effects on insulin secre- emptying and stimulate β-cell proliferation. tion and blood glucose, often leading to One of the most promising GLP-1 receptor weight gain. agonists is exenatide (exendin-4) which is 3) The biguanides (e.g. metformin) are a 53% identical to human GLP-1 at the amino class of drugs that lower blood glucose acid level. The main advantage of exenatide ACCORDING TO THE WHO, THE NUMBER OF PEOPLE LIVING WITH DIABETES HAS ALMOST QUADRU- PLED SINCE 1980 TO 422 MILLION ADULTS.

7 Peptides and Diabetes

In the 1970s, is its resistance to cleavage and inactiva- degludec was approved in Europe in 2015 the insulin tion by dipeptidyl-peptidase IV (DPP IV). for treatment of children and adolescents receptor was In 2005, the FDA approved exenatide as with diabetes. discovered, and adjunctive therapy to improve blood sugar 9) C-Peptide is biologically active. Clini- 10 years later, its tyrosine control in patients with type 2 diabetes who cal studies showed that administration of kinase activity have not achieved adequate control with C-peptide to diabetes type 1 patients lack- was demon- metformin and/or a sulfonylurea. Use of ing the peptide alleviates nerve and renal strated. the peptide as primary monotherapy was dysfunctions associated with the disease. A approved in 2009, and a sustained release long-acting analog, PEGylated C-peptide, is formulation in 2014. under evaluation. The long-acting GLP-1 agonist liraglutide was approved by the authority for the treat- Prospects ment of type 2 diabetes in 2010. Although some of the agents described Albiglutide, a DPP IV-resistant GLP-1 dimer above are still in the early phases of investi- bound to albumin was approved by both gation, there is little doubt that the therapy FDA and European authorities in 2014. of diabetes will undergo major changes in FDA-approved dulaglutide is a GLP-1 dimer the near future. It is important to diagnose linked to human immunoglobulin G4. Their all type 2 diabetics at an earlier stage (for half-lifes, 4 - 7 days, are in the same range example by making self monitoring of blood as the half-life of the recently developed glucose easier) and begin treatment in an GLP-1 analog semaglutide, These peptides attempt to minimize the diabetes-associat- are considerably more stable than exena- ed complications. tide, The identification of the genetic compo- 6) DPP IV inhibitors represent another nents of type 1 and type 2 diabetes is an approach for the treatment of diabetes. Si- important area of research, because eluci- tagliptin is the first candidate of this novel dation of the diabetes genes will influence class of antihyperglycemic agents that all efforts towards an understanding of the has been approved by the FDA. Alogliptin, disease, its complications, and its treat- linagliptin, saxagliptin, and vildagliptin have ment, cure, and prevention. For this reason, been approved in the USA and in various genomic DNA from subjects with severe countries worldwide. These DPP IV inhibi- insulin resistance has been screened for tors can be used either alone or in combi- mutations in genes that are implicated nation with other oral antihyperglycemic in insulin signaling. Indeed, a mutation in agents (such as metformin or a thiazolidine the gene encoding the serine/threonine -dione) for treatment of diabetes mellitus kinase AKT2 (also known as PKBβ) could type 2. be identified. AKT2 is highly expressed in 7) Pramlintide, a soluble amylin analog, has insulin-sensitive tissues and has been gained FDA approval as an adjunct to in- implicated in insulin-regulated glucose sulin therapy in type 1 and type 2 diabetes. uptake into muscle and fat cells by promot- Like amylin, pramlintide acts centrally and ing the translocation of glucose transporter decreases glucagon secretion, slows gastric 4 (GLUT4) to the cell surface. emptying and induces satiety. Advances in genomics, proteomics and 8) Insulin therapy is also indicated in metabolomics will help us to further un- the treatment of type 2 diabetes for the derstand the causes of type 1 and type 2 management of severe hyperglycemia after diabetes and could eventually lead to novel failure of oral agents. Long-acting insulin therapeutic approaches. analogs could be obtained by replacement of Asn21 (A-chain) by glycine and addition of two arginine residues (insulin glargine) or acylation of lysine29 (B-chain) with long-chain fatty acids. Insulin degludec is obtained by palmitoylation, which distinctly improves the metabolic stability of the peptide hormone by hexamer formation. Insulin

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9 Peptides and Diabetes

J.F. List and J.F. Habener K. Fujioka R. Gupta et al. Glucagon-like peptide 1 agonists Pathophysiology of type 2 diabetes Emerging drug candidates of dipep- and the development and growth of and the role of incretin hormones tidyl peptidase IV (DPP IV) inhibitor pancreatic beta-cells. and beta-cell dysfunction. class for the treatment of type 2 Am. J. Physiol. Endocrinol. Metab. JAAPA Suppl, 3-8 (2007) diabetes. 286, E875-E881(2004) R. Gadsby Curr. Drug Targets 10, 71-87 (2009) L.L. Nielsen et al. New treatments for type 2 diabetes F.K. Knop et al. Pharmacology of exenatide (syn- - the DPP4 inhibitors. Incretin-based therapy of type 2 thetic exendin-4): a potential thera- Prim. Care Diabetes 1, 209-211 diabetes mellitus. peutic for improved glycemic control (2007) Curr. Protein Pept. Sci. 10, 46-55 of type 2 diabetes. J. Meece (2009) Regul. Peptides 117, 77-88 (2004) Pancreatic islet dysfunction in type T. Salvatore et al. A. Nourparvar et al. 2 diabetes: a rational target for Progress in the oral treatment of Novel strategies for the pharma- incretin-based therapies. type 2 diabetes: update on DPP-IV cological management of type 2 Curr. Med. Res. Opin. 23, 933-944 inhibitors. diabetes. (2007) Curr. Diabetes Rev. 5, 92-101 (2009) Trends Pharmacol. Sci. 25, 86-91 J. Wahren et al. W. Benalla et al. (2004) C-Peptide is a bioactive peptide. Antidiabetic medicinal plants as a S.M. Rangwala and M.A. Lazar Diabetologia 50, 503-509 (2007) source of alpha glucosidase inhibi- Peroxisome proliferator-activated A.M. Abbatecola et al. tors. receptor γ in diabetes and metabo- New approaches to treating type 2 Curr. Diab. Rev. 6 247-254 (2010) lism. diabetes mellitus in the elderly: role M. Christensen and F.K. Knop Trends Pharmacol. Sci. 25, 331-336 of incretin therapies. Once-weekly GLP-1 agonists: How (2004) Drugs Aging 25, 913-925 (2008) do they differ from exenatide and Y. Sato et al. S.E. Inzucchi and D.K. McGuire liraglutide? C-peptide fragments stimulate glu- New drugs for the treatment of dia- Curr. Diab. Rep. 10, 124-132 (2010) cose utilization in diabetic rats. betes: part II: Incretin-based therapy B. Gallwitz Cell. Mol. Life Sci. 61, 727-732 (2004) and beyond. Benefit-risk assessment of exena- T.P. Vahl and D.A. D‘Alessio Circulation 117, 574-584 (2008) tide in the therapy of type 2 diabetes Gut peptides in the treatment of A.M. Lambeir et al. mellitus. diabetes mellitus. DPP4 inhibitors for diabetes - what Drug Saf. 33, 87-100 (2010) Expert. Opin. Investig. Drugs. 13, 177- next? J. Gerich 188 (2004) Biochem. Pharmacol. 76, 1637-1643 DPP-4 inhibitors: what may be the J.F. Gautier et al. (2008) clinical differentiators? Biological actions of the incretins N. Mikhail Diabetes Res. Clin. Pract. 90, 131- GIP and GLP-1 and therapeutic Incretin mimetics and dipeptidyl 140 (2010) perspectives in patients with type 2 peptidase 4 inhibitors in clinical Y. Seino et al. diabetes. trials for the treatment of type 2 GIP and GLP-1, the two incretin hor- Diabetes Metab. 31, 233-242 (2005) diabetes. mones: Similarities and differences. E.M. Sinclair and D.J. Drucker Expert Opin. Investig. Drugs 17, 845- J. Diabetes Investig. 1, 8-23 (2010) Proglucagon-derived peptides: 853 (2008) B. Ahren mechanisms of action and thera- Y. Ng et al. The future of incretin-based therapeutic potential. Rapid activation of Akt2 is sufficient py: novel avenues - novel targets. Physiology 20, 357-365 (2005) to stimulate GLUT4 translocation in Diabetes Obes. Metab. 13 Suppl 1, D.J. Drucker and M.A. Nauck 3T3-L1 adipocytes. 158-166 (2011) The incretin system: glucagon-like Cell. Metab. 7, 348-356 (2008) M.J. Davies et al. peptide-1 receptor agonists and P.R. Flatt et al. Liraglutide - overview of the preclini- dipeptidyl peptidase-4 inhibitors in Recent advances in antidiabetic cal and clinical data and its role in type 2 diabetes. drug therapies targeting the entero- the treatment of type 2 diabetes. Lancet 368, 1696-1705 (2006) insular axis. Diabetes Obes. Metab. 13, 207-220 Curr. Drug Metab. 10, 125-137 (2009) (2011)

10 B. Gallwitz S. Calanna et al. As with humans, diabe- GLP-1 agonists and dipeptidyl-pep- Secretion of Glucose-Dependent tes has become a grow- tidase IV inhibitors. Insulinotropic Polypeptide in ing problem with dogs and cats in recent years Handb. Exp. Pharmacol. 53-74 (2011) Patients With Type 2 Diabetes. due to their increasing D.M. Irwin and K.J. Prentice Diabetes Care 36. 3346-3352 (2013) life expectancy in com- Incretin hormones and the ex- G. Grunberger bination with obesity panding families of glucagon-like Novel therapies for the management and lack of exercise. sequences and their receptors. of type 2 diabetes mellitus: part 1. Diabetes Obes. Metab. 13 Suppl 1, pramlintide and bromocriptine-QR. 69-81 (2011) J. Diabetes 5,110-117 (2013) G.J. Ryan and Y. Hardy International Diabetes Federation Liraglutide: once-daily GLP-1 IDF Diabetes Atlas (6th ed.) agonist for the treatment of type 2 (2013) diabetes. N. Irwin and P.R. Flatt J. Clin. Pharm. Ther. 36, 260-274 Enteroendocrine hormone mimet- (2011) ics for the treatment of obesity and J. Shubrook et al. diabetes. Saxagliptin: A Selective DPP-4 Curr. Opin. Pharmacol. 13, 989-995 Inhibitor for the Treatment of Type 2 (2013) Diabetes Mellitus. K. Pillai and P. Govender Clin. Med. Insights Endocrinol. Diabe- Amylin uncovered: a review on the tes 4, 1-12 (2011) polypeptide responsible for type II P. Westermark et al. diabetes. Islet amyloid polypeptide, islet amy- Biomed. Res. Int. 2013, 826706 loid, and diabetes mellitus. (2013) Physiol. Rev. 91, 795-826 (2011) D. Bataille and S. Dalle K. Hunter and C. Holscher The forgotten members of the gluca- Drugs developed to treat diabetes, gon family. liraglutide and lixisenatide, cross Diabetes Res. Clin. Pract. 106,1-10 the blood brain barrier and enhance (2014) neurogenesis. S.L. Booth et al. BMC Neurosci. 13, 33 (2012) Bone as an endocrine organ relevant M.A. Jackson et al. to diabetes. Stable liquid glucagon formulations Curr. Diab. Rep. 14, 556 (2014) for rescue treatment and bi-hor- C. Chakraborty et al. monal closed-loop pancreas. Understanding the molecular Curr. Diab. Rep. 12, 705-710 (2012) dynamics of type-2 diabetes drug N.R. Pinelli et al. target DPP-4 and its interaction with Despite the steady Exogenous glucagon-like peptide-1 Sitagliptin and inhibitor Diprotin-A. progress in research, the dramatic spread of for hyperglycemia in critically ill Cell. Biochem. Biophys. 70, 907-922 diabetes mellitus which patients. (2014) is observed throughout Ann. Pharmacother. 46, 124-129 S. Chowdhury et al. the world remains one (2012) Xenin-25 delays gastric emptying of the most challeng- A. Pocai and reduces postprandial glucose ing health problems of Unraveling oxyntomodulin, GLP1’s levels in humans with and without the 21st century. Today, enigmatic brother. type 2 diabetes. diabetes mellitus is one of the main causes of J. Endocrinol. 215, 335-346 (2012) Am. J. Physiol. Gastrointest. Liver death in most devel- B.M. Wice et al. Physiol. 306, G301-G309 (2014) oped countries. Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes 61, 1793-1800 (2012)

11 Peptides and Diabetes

R.E. George and S. Joseph D.L. Hay et al. S.L. Anderson and J.M. Trujillo A review of newer treatment ap- Amylin: Pharmacology, Physiology, Lixisenatide in type 2 diabetes: lat- proaches for type-2 diabetes: Focus- and Clinical Potential. est evidence and clinical usefulness. ing safety and efficacy of incretin Pharmacol. Rev. 67, 564-600 (2015) Ther. Adv. Chronic Dis. 7, 4-17 (2016) based therapy. I. Kanazawa O. Bouttefeux et al. Saudi Pharm. J. 22, 403-410 (2014) Osteocalcin as a hormone regulating Delivery of Peptides Via the Oral C.F. Godfredsen et al. glucose metabolism. Route: Diabetes Treatment by T he human GLP-1 analogs lira- World J. Diabetes 6,1345-1354 Peptide-Loaded Nanoparticles. glutide and semaglutide: absence (2015) Curr. Pharm. Des. 22, 1161-1176 of histopathological effects on the J. Lau et al. (2016) pancreas in nonhuman primates. Discovery of the Once-Weekly S. Kalra et al. Diabetes 6. 2486-2497 (2014) Glucagon-Like Peptide-1 (GLP-1) Glucagon-like peptide-1 receptor A.F. Godoy-Matos Analogue Semaglutide. agonists in the treatment of type The role of glucagon on type 2 diabe- J. Med. Chem. 58, 7370-7380 (2015) 2 diabetes: Past, present, and future. tes at a glance. C. Liu et al. Indian J. Endocrinol. Metab. 20, 254- Diabetol. Metab. Syndr. 6, 91 (2014) N-Acetyl Cysteine improves the dia- 267 (2016) L. Juillerat-Jeanneret betic cardiac function: possible role C.Y. Lee Dipeptidyl peptidase IV and its of fibrosis inhibition. Glucagon-Like Peptide-1 Formula- inhibitors: therapeutics for type 2 BMC Cardiovasc. Disord. 15, 84 tion - the Present and Future Devel- diabetes and what else? (2015) opment in Diabetes Treatment. J. Med. Chem. 57, 2197-2212 (2014) F. Mittermeyer et al. Basic Clin. Pharmacol. Toxicol. 118, S.E. Kahn et al. Addressing unmet medical needs in 173-180 (2016) Pathophysiology and treatment of type 2 diabetes: a narrative review of L. Li et al. type 2 diabetes: perspectives on the drugs under development. Dipeptidyl peptidase-4 inhibitors past, present, and future. Curr. Diabetes Rev. 11, 17-31 (2015) and risk of heart failure in type 2 Lancet 383, 1068-1083 (2014) D.A. Sandoval and D.A. D’Alessio diabetes: systematic review and R.W. Nelson and C.E. Reusch Physiology of proglucagon peptides: meta-analysis of randomised and Animal models of disease: classi- role of glucagon and GLP-1 in health observational studies. fication and etiology of diabetes in and disease. BMJ 352, i610 (2016) dogs and cats. Physiol. Rev. 95, 513-548 (2015) M.G. Minze and L.M. Chastain J. Endocrinol. 222, T1-T9 (2014) J.A. Shaw et al. Combination therapies in the man- A. Pocai C-peptide as a Therapy for Kidney agement of type 2 diabetes: the use Action and therapeutic potential of Disease: A Systematic Review and of insulin degludec/liraglutide. oxyntomodulin. Meta-Analysis. Ther. Clin. Risk Manag. 12, 471-478 Mol. Metab. 3, 241-251 (2014) PLoS ONE 10, e0127439 (2015) (2016) M. Rigato and G.P. Fadini M. Visa et al. R.G. Mirmira et al. Comparative effectiveness of lira- Islet amyloid polypeptide exerts a Biomarkers of beta-Cell Stress and glutide in the treatment of type 2 novel autocrine action in beta-cell Death in Type 1 Diabetes. diabetes. signaling and proliferation. Curr. Diab. Rep. 16, 95 (2016) Diabetes Metab. Syndr. Obes. 7, 107- FASEB J. 29, 2970-2979 (2015) A.K. Sharma et al. 120 (2014) L. Whiting et al. Albiglutide: Is a better hope against G. Umpierrez et al. Glicentin-related pancreatic poly- diabetes mellitus? Efficacy and safety of dulaglutide peptide inhibits glucose-stimulated Biomed. Pharmacother. 77, 120-128 monotherapy versus metformin in insulin secretion from the isolated (2016) type 2 diabetes in a randomized pancreas of adult male rats. L. Sobrevia et al. controlled trial (AWARD-3). Physiol. Rep. 3 (2015) Insulin Is a Key Modulator of Feto- Diabetes Care 37, 2168-2176 (2014) L. Zhong et al. placental Endothelium Metabolic H.A. Blair and G.M. Keating Recent Advances in Dipeptidyl-Pep- Disturbances in Gestational Diabe- Albiglutide: a review of its use in pa- tidase-4 Inhibition Therapy: Lessons tes Mellitus. tients with type 2 diabetes mellitus. from the Bench and Clinical Trials. Front. Physiol. 7, 119 (2016) Drugs 75, 651-663 (2015) J. Diabetes Res. 606031 (2015)

12 PEPTIDES FOR DIABETES RESEARCH Bachem offers peptidic active pharmaceutical ingredients (generic APIs) and Clinalfa® basic ready-to-use formulations, sterile products for approved clinical studies, please see page 22 or go to www.bachem.com

13 Peptides and Diabetes

Amylin (human) Amylin (14-20) (human) NEW AMYLIN 4030200 4099428 KCNTATCATQRLANFLVHSSN- NFLVHSS (IAPP) NFGAILSSTNVGSNTY-NH 2 Amylin (20-29) (human) Amylin (free acid) (human) NEW 4030350 4073878 SNNFGAILSS KCNTATCATQRLANFLVHSSN- NFGAILSSTNVGSNTY Amylin (mouse, rat) 4030201 Biotinyl-Amylin (human) KCNTATCATQRLANFLVRSSNNLGPV-

4059629 LPPTNVGSNTY-NH2 Biotinyl-KCNTATCATQRLANFLVHSSN-

NFGAILSSTNVGSNTY-NH2 Biotinyl-Amylin (mouse, rat) 4089772 5-FAM-Amylin (human) Biotinyl-KCNTATCATQRLANFLVRSSNN-

4089771 LGPVLPPTNVGSNTY-NH2 Fluorescein-5-carbonyl-KCNTATCATQR-

LANFLVHSSNNFGAILSSTNVGSNTY-NH2 5-FAM-Amylin (mouse, rat) 4089773 Amylin (1-13) (human) Fluorescein-5-carbonyl-KCNTATCATQR- 4039860 LANFLVRSSNNLGPVLPPTNVGSNTY-

KCNTATCATQRLA NH2

Amylin (8-37) (human) Amylin (8-37) (mouse, rat) 4030202 4030346 ATQRLANFLVHSSNNFGAILSSTNVGSN- ATQRLANFLVRSSNNLGPVLPPTNVGSN-

TY-NH2 TY-NH2

Acetyl-Amylin (8-37) (human) 4030345 Ac-ATQRLANFLVHSSNNFGAILSSTNVG-

SNTY-NH2

(Tyr0)-C-Peptide (dog) (Tyr0)-C-Peptide (human) C-PEPTIDE 4030533 4034546 YEVEDLQVRDVELAGAPGEGGLQPLALE- YEAEDLQVGQVELGGGPGAGSLQPLA- GALQ LEGSLQ

7·10 C-Peptide (human) NEW ([D8]Val )-C-Peptide (human) (Acetate salt) 4028385

4068086 EAEDLQ[D8]VGQ[D8]VELGGGPGAGSLQ- EAEDLQVGQVELGGGPGAGSLQPLALEG- PLALEGSLQ SLQ (Acetate salt) Proinsulin C-Peptide (55-89) C-Peptide (human) (human) (Trifluoroacetate salt) 4011662 4009494 RREAEDLQVGQVELGGGPGAGSLQPLA- EAEDLQVGQVELGGGPGAGSLQPLALEG- LEGSLQKR SLQ (trifluoroacetate salt)

14 Tyr-Proinsulin C-Peptide (55-89) C-Peptide 2 (rat) C-PEPTIDE (human) 4035984 4015509 EVEDPQVAQLELGGGPGAGDLQTLAL- (CONTINUED) YRREAEDLQVGQVELGGGPGAGSLQPLA- EVARQ LEGSLQKR C-Peptide 1 (rat) 4045921 EVEDPQVPQLELGGGPEAGDLQTLAL- EVARQ

Exenatide (Des-Gly2)-Exenatide EXENDIN (Exendin-4) 4072221 4019602 HEGTFTSDLSKQMEEEAVRLFIEWLKNG-

HGEGTFTSDLSKQMEEEAVRL- GPSSGAPPPS-NH2

FIEWLKNGGPSSGAPPPS-NH2 Endo-38a-Pro-Exenatide Acetyl-Exenatide 4072223 4072222 HGEGTFTSDLSKQMEEEAVRL-

Ac-HGEGTFTSDLSKQMEEEAVRL- FIEWLKNGGPPSSGAPPPS-NH2

FIEWLKNGGPSSGAPPPS-NH2 (D-His1)-Exenatide (D-Asn28)-Exenatide 4072224 4084643 hGEGTFTSDLSKQMEEEAVRL-

HGEGTFTSDLSKQMEEEAVRL- FIEWLKNGGPSSGAPPPS-NH2 FIEWLKNGGPSSGAPPPS-NH₂ (Met(O)¹⁴)-Exenatide (Asp28)-Exenatide (Exendin-4 sulfoxide) 4085312 4082706 * Bachem provides this product HGEGTFTSDLSKQMEEEAVRLFIEWLK HGEGTFTSDLSKQM(O)EEEAVRL- solely for uses within the scope of nGGPSSGAPPPS-NH₂ FIEWLKNGGPSSGAPPPS-NH2 any statute or law providing for an immunity, exemption, or exception (D-Asp28)-Exenatide (Glu⁹)-Exenatide (2-39) NEW to patent infringement (“Exempted Uses”), including but not limited to 35 4085313 4095258 U.S.C. § 271(e)(1) in the United States, HGEGTFTSDLSKQMEEEAVRLFIEWLK- GEGTFTSELSKQMEEEAVRLFIEWLKNG- the Bolar type exemption in Europe, dGGPSSGAPPPS-NH₂ GPSSGAPPPS-NH2 and any corresponding exception to patent infringement in any other (β-Asp28)-Exenatide Exendin-3 country. It is the sole responsibility of the purchaser or user of this product, 4085314 4015051 and the purchaser or user of this HGEGTFTSDLSKQMEEEAVRLFIEWLK HSDGTFTSDLSKQMEEEAVRL- product agrees to engage only in D(GGPSSGAPPPS-NH₂) FIEWLKNGGPSSGAPPPS-NH2 such Exempted Uses, and to comply with all applicable intellectual (β-D-Asp28)-Exenatide NEW Exendin-4 (1-8) property laws and/or regulations. The purchaser of this product agrees to 4085315 4051740 indemnify Bachem against all claims HGEGTFTSDLSKQMEEEAVRLFIEWLK HGEGTFTS-NH2 in connection with the performance d(GGPSSGAPPPS-NH₂) of the respective commercial agree- Exendin-4 (3-39) ment (e.g. supply agreement) and 4027457 possible infringements of intellectual property rights. EGTFTSDLSKQMEEEAVRLFIEWLKNGG-

PSSGAPPPS-NH2

15 Peptides and Diabetes

Exendin (9-39) Lixisenatide* EXENDIN 4017799 ((Des-Pro³⁸)-Exendin-4(-Lys)₆ amide) DLSKQMEEEAVRLFIEWLKNGGPSS- 4084106 (CONTINUED) GAPPPS-NH HGEGTFTSDLSKQMEEEAVRL- 2

FIEWLKNGGPSSGAPPSKKKKKK-NH2

Gastric Inhibitory Polypeptide (human) Gastric Inhibitory Polypeptide GLUCOSE- (Glucose-Dependent Insulinotropic (porcine) Polypeptide (human), GIP (human)) 4012268 DEPENDENT 4030658 YAEGTFISDYSIAMDKIRQQDFVNWL- YAEGTFISDYSIAMDKIHQQDFVNWL- LAQKGKKSDWKHNITQ INSULINO- LAQKGKKNDWKHNITQ Gastric Inhibitory Polypeptide (1-30) TROPIC (D-Ala²)-Gastric Inhibitory Polypeptide amide (porcine) (human) NEW (Glucose-Dependent Insulinotropic POLYPEPTIDE 4054476 Polypeptide (porcine), GIP (porcine)) YaEGTFISDYSIAMDKIHQQDFVNWL- 4030659 (GIP) LAQKGKKNDWKHNITQ YAEGTFISDYSIAMDKIRQQDFVNWL-

LAQK-NH2 (Pro³)-Gastric Inhibitory Polypeptide (human) NEW Gastric Inhibitory Polypeptide (3-42) 4062141 (human) YAPGTFISDYSIAMDKIHQQDFVNWL- 4034653 LAQKGKKNDWKHNITQ EGTFISDYSIAMDKIHQQDFVNWLLAQK- GKKNDWKHNITQ Gastric Inhibitory Polypeptide (6-30) amide (human) 4040632

FISDYSIAMDKIHQQDFVNWLLAQK-NH2

Glucagon (1-29) (human, rat, porcine) Biotinyl-Glucagon (1-29) GLUCAGON, 4033017 (human, rat, porcine) HSQGTFTSDYSKYLDSRRAQD- 4034566 GRPP, FVQWLMNT Biotinyl-HSQGTFTSDYSKYLDSRRAQD- FVQWLMNT OXYNTO- Glucagon (1-29) (human, rat, porcine) (Acetate salt) NEW (Asp28)-Glucagon (1-29) MODULIN 4088814 (human, rat, porcine) NEW HSQGTFTSDYSKYLDSRRAQD- 4079056 FVQWLMNT HSQGTFTSDYSKYLDSRRAQDFVQWLMDT (Acetate salt) (Glu³)-Glucagon (1-29) 13 14 ([ C6]Leu )-Glucagon (1-29) (human, rat, porcine) NEW (human, rat, porcine) 4079054 4072022 HSEGTFTSDYSKYLDSRRAEDFVQWLMNT 13 HSQGTFTSDYSKY[ C6]LDSRRAQD- FVQWLMNT

16 (Glu²⁰)-Glucagon (1-29) Glucagon (19-29) GLUCAGON, (human, rat, porcine) NEW (human, rat, porcine) 4079055 4030650 GRPP, HSQGTFTSDYSKYLDSRRAED- AQDFVQWLMNT FVQWLMNT OXYNTO- GRPP (human) ((Glu²⁴)-Glucagon (1-29) (Glicentin-Related Polypeptide MODULIN (human, rat, porcine) NEW (human)) 4071253 4044528 (CONTINUED) HSQGTFTSDYSKYLDSRRAQDFVEW- RSLQDTEEKSRSFSASQADPLSDP- LMNT DQMNED

(Des-His¹,Glu⁹)-Glucagon (1-29) amide Oxyntomodulin (human, mouse, rat) (human, rat, porcine)) (Glucagon-37 (human, mouse, rat)) 4030635 4044527 SQGTFTSEYSKYLDSRRAQDFVQWLMNT- HSQGTFTSDYSKYLDSRRAQD- NH₂ FVQWLMNTKRNRNNIA

(Des-Thr5)-Glucagon Oxyntomodulin (30-37) 4045345 (bovine, dog, porcine) HSQGFTSDYSKYLDSRRAQDFVQWLMNT 4012614 KRNKNNIA (Des-Thr7)-Glucagon 4045365 HSQGTFSDYSKYLDSRRAQDFVQWLMNT

(Met(O)27)-Glucagon (1-29) (human, rat, porcine) 4043506 HSQGTFTSDYSKYLDSRRAQDFVQWLM (O)NT

GLP-1 (1-36) amide (human, bovine, GLP-1 (7-36) amide (human, bovine, GLUCAGON- guinea pig, mouse, rat) guinea pig, mouse, rat) 4030651 4030663 LIKE HDEFERHAEGTFTSDVSSYLEGQAAKE- HAEGTFTSDVSSYLEGQAAKEFIAWLVK- FIAWLVKGR-NH GR-NH PEPTIDES 2 2 GLP-1 (1-37) (human, bovine, GLP-1 (7-36)-Lys(biotinyl) amide (hu- guinea pig, mouse, rat) man, bovine, guinea pig, mouse, rat) 4037542 4042611 HDEFERHAEGTFTSDVSSYLEGQAAKEFI- HAEGTFTSDVSSYLEGQAAKEFIAWLVKG

AWLVKGRG RK(biotinyl)-NH2

GLP-1 (7-36) amide GLP-1 (7-36)-Lys(6-FAM) amide (hu- (chicken, common turkey) man, bovine, guinea pig, mouse, rat) 4040190 4042610 HAEGTYTSDITSYLEGQAAKEFIAWLVN- HAEGTFTSDVSSYLEGQAAKEFIAWLVKG

GR-NH2 RK(fluorescein-6-carbonyl)-NH2

17 Peptides and Diabetes

(Ser8)-GLP-1 (7-36) amide (human, GLP-2 (1-33) (human) GLUCAGON- bovine, guinea pig, mouse, rat) (Ammonium acetate salt) NEW 4029130 4095874 LIKE HSEGTFTSDVSSYLEGQAAKEFIAWLVK- HADGSFSDEMNTILDNLAARDFIN- GR-NH₂ WLIQTKITD PEPTIDES (Ammonium acetate salt) GLP-1 (7-37) (human, bovine, guinea (CONTINUED) pig, mouse, rat) (Acetate salt) GLP-2 (1-33) (human) 4043014 (Trifluoroacetate salt) HAEGTFTSDVSSYLEGQAAKEFIAWLVK- 4039611 GRG HADGSFSDEMNTILDNLAARDFIN- (Acetate salt) WLIQTKITD (Trifluoroacetate salt) GLP-1 (7-37) (human, bovine, guinea pig, mouse, rat) GLP-2 (1-34) (human) (Trifluoroacetate salt) 4029353 4034865 HADGSFSDEMNTILDNLAARDFIN- HAEGTFTSDVSSYLEGQAAKEFIAWLVK- WLIQTKITDR GRG (Trifluoroacetate salt) GLP-2 (rat) 4034866 GLP-1 (9-36) amide (human, bovine, HADGSFSDEMNTILDNLATRDFIN- guinea pig, mouse, porcine, rat) WLIQTKITD 4027697 EGTFTSDVSSYLEGQAAKEFIAWLVKGR-

NH2

Semaglutide* NEW (NN9535, (Aib2, Lys(γ-Glu-AEEAc-AEEAc -17-carboxy-heptadecanoyl)²⁶,Arg³⁴)- GLP-1 (7-37)) 4091661 H-Aib- EGTFTSDVSSYLEGQAAK(γE(AEEAc- AEEAc-17-carboxyheptadecanoyl)) EFIAWLVRGRG * Bachem provides this product solely for uses within the scope of any statute or law providing for an immunity, exemption, or exception to patent infringement (“Ex- empted Uses”), including but not limited to 35 U.S.C. § 271(e)(1) in the United States, the Bolar type exemption in Europe, and any corresponding exception to patent infringement in any other country. It is the sole responsibility of the purchaser or user of this product, and the purchaser or user of this product agrees to engage only in such Exempted Uses, and to comply with all applicable intellectual property laws and/or regulations. The purchaser of this product agrees to indemnify Bachem against all claims in connection with the performance of the respective commercial agreement (e.g. supply agreement) and possible infringements of intellectual property rights.

18 rec IGF-I (human) IGF-II (33-40) INSULIN, 4030778 4030781 SRVSRRSR INSULIN-LIKE IGF-I Analog 4018631 Lys-Lys-IRS-1 (891-902) GROWTH CYAAPLKPAKSC (dephosphorylated) (human) (Disulfide bond) 4046873 FACTOR KKKSPGEYVNIEFG IGF-I (1-3) (IGF) 4026104 Insulin B (22-25) GPE 4004735 RGFF IGF-I (24-41) 4030780 YFNKPTGYGSSSRRAPQT

rec IGF-II (1-67) (human) 4030639 AYRPSETLCGGELVDTLQFVCGDRGFYFS- RPASRVSRRSRGIVEECCFRSCDLALLE- TYCATPAKSE

H-Gly-Pro-AMC · HBr Diprotin A RELATED 4002520 4009723 PRODUCTS: GP-AMC · HBr IPI H-Gly-Pro-4MβNA Diprotin B DPP IV 4000721 4009528 SUBSTRATES GP-MNA VPL

H-Gly-Pro-βNA AND 4000551 INHIBITORS GP-bNA H-Gly-Pro-pNA · HCl 4025614 GP-pNA · HCl

H-Gly-Pro-pNA · p-tosylate 4003654 GP-pNA · p-tosylate

19 Peptides and Diabetes

Adropin (34-76) (human, mouse, rat) Preptin (human) RELATED 4064212 4059088 CHSRSADVDSLSESSPNSSPGPCPE- DVSTPPTVLPDNFPRYPVGKFFQYDT- PRODUCTS: KAPPPQKPSHEGSYLLQP WKQSTQRL

PEPTIDES (Pyr1)-Apelin-13 (human, bovine, Preptin (rat) mouse, rat) 4050843 4029110 DVSTSQAVLPDDFPRYPVGKFFKFDT-

Calcitonin (8-32) (salmon I) Pseudin-2 4037182 4060547

VLGKLSQELHKLQTYPRTNTGSGTP-NH2 GLNALKKVFQGIHEAIKLINNHVQ

Acetyl-(Asn³⁰,Tyr³²)-Calcitonin (8-32) TRH (salmon I) (Protirelin) (AC187) 4038214

4034543

L-Carnosine

Endotrophin (mouse) 4085553 TEPLFLTKTDICKLSRDAGTCVDFKLL- WHYDLESKSCKRFWYGGCGGNENRFH- SQEECEKMCSPELTV (Disulfide bonds, air oxidized)

Osteocalcin (1-49) (human) 4034491 YLYQWLGAPVPYPDPL-Gla-PRR-Gla-VC- Gla-LNPDCDELADHIGFQEAYRRFYGPV (Disulfide bond)

(Glu¹⁷·²¹·²⁴)-Osteocalcin (1-49) (human) NEW (Osteocalcin (1-49) (human) (decarboxylated)) 4063516 YLYQWLGAPVPYPDPLEPRREVCELNP- DCDELADHIGFQEAYRRFYGPV (Disulfide bond) Pancreastatin (33-48) (human) 4055812

EEEEEMAVVPQGLFRG-NH2

20 PRODUCT BROCHURES

21 Peptides and Diabetes

Exenatide Acetate Lixisenatide* GENERIC 4044219 4041774 HGEGTFTSDLSKQMEEEAVRL- HGEGTFTSDLSKQMEEEAVRL- APIs FIEWLKNGGPSSGAPPPS-NH FIEWLKNGGPSSGAPPSKKKKKK-NH₂ 2

Glucagon 4033017-GMP HSQGTFTSDYSKYLDSRRAQD- FVQWLMNT

* Bachem provides this product solely for uses within the scope of any statute or law providing for an immunity, exemption, or exception to patent infringement (“Exempted Uses”), including but not limited to 35 U.S.C. § 271(e)(1) in the United States, the Bolar type exemption in Europe, and any corresponding exception to patent infringement in any other country. It is the sole responsibility of the purchaser or user of this product, and the purchaser or user of this product agrees to engage only in such Exempted Uses, and to comply with all applicable intellectual property laws and/or regulations. The purchaser of this product agrees to indemnify Bachem against all claims in connection with the performance of the respective commercial agreement (e.g. supply agreement) and possible infringements of intellectual property rights.

22 LIVER CELL Liver cell. Colored transmission electron micrograph (TEM) of a section through a hepatocyte liver cell, showing smooth endoplasmic reticulum (red), glycogen granules (grey) and peroxisomes (green).

(KEYSTONE/SCIENCE PHOTO LIBRARY)

23 Some products may berestricted countries. incertain We cannot bemadeliable for any possible errors ormisprints. All information iscompiled to thebest of ourknowledge. shop.bachem.com or shoponline www.bachem.com Visit ourwebsite [email protected] Tel. +41585952020 Bachem Europe, Africa, Middle East andIndia [email protected] AG Tel. +81366610774 K.K. Bachem Japan Asia Pacific [email protected] +1 3105394171 Tel. +1 8884222436(toll free inUSA &Canada) Bachem Americas, Inc. Americas Marketing &Sales Contact www.bachem.com shop.bachem.com

2003740 published by Global Marketing, Bachem AG, May 2020