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 hypergly- cemia, 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 re- sults 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 dia- betes’, 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 insulinotro- pic 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 lates breakdown of Stimu glycogen 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 se- cretion 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.