Peptides are formed when two amino acids join together by the carboxyl group of one and the amine group of the second. A water molecule is removed in the process.
The C-N bond between the two separate amino acids is called a peptide bond, which implies the existence of the peptide group, which is commonly written in text as -CONH-
Two molecules linked by a peptide bond become what are called a dipeptide, while a chain of molecules linked by peptide bonds is called a polypeptide. A protein is made up of one or more polypeptide-chains, each of which consists of amino acids. Instead of writing complex formulae, sequences of amino acids are commonly written using three or one-letter codes (e.g. ala-gly-val-leu-phe (3 letter) or AGVLF (1 letter)).
Peptides for diabetic patients
Some recently developed peptides are used as medicines for diabetic patients. Current pharmacological treatment of late-stage type 2 diabetes typically consists of replacement of only one of the peptide hormones that are lost after ß-cell destruction, namely insulin. It is believed that insulin resistance and declining ß-cell function are caused and exacerbated by multiple underlying hormone deficits and that metabolic abnormalities may be reversed and corrected by administering novel natural peptide hormones in co-replacement therapies.
Professor Garth Cooper and his team have discovered two new peptide hormones implicated in diabetes. The team is expected to identify more as the company's discovery research continues. The first of these, EN122001, is believed to increase insulin secretion. The second, EN122002, is thought to mediate glucose uptake and may act as a novel islet ß-cell growth factor.
Glutamic acid decarboxylase (GAD) 65 is a major autoantigen in type 1 diabetes. Regions of homology exist between GAD65 (residues 250-273) and coxsackie P2-C protein (residues 28-50), apart from GAD65 (residues 506-518) and proinsulin (residues 24-36). Each of these has been reported to be a diabetes-associated T cell target. The aim of this study was to determine whether the homologous regions are shared targets of T lymphocyte reactivity in individual patients with type 1 diabetes. T cell proliferation against the corresponding peptide pairs, GAD254-276 and coxsackie P2-C32-54, and GAD506-518 and proinsulin24-36, were measured in peripheral blood mononuclear cells from 26 patients with newly diagnosed type 1 diabetes and 24 control subjects. Responses with stimulation indices higher than 3 were found against each of the antigens tested in both patients and control subjects, and no differences were observed between groups. A strong positive correlation was found between responses to the corresponding peptide pairs GAD254-276 and coxsackie P2-C32-54 (r=0.77, P<0.0001), and between responses to the corresponding peptide pairs GAD506-518 and proinsulin24-36 (r=0.66, P<0.0001).
However, a similar correlation was also observed between responses to the non-corresponding pairs coxsackie P2-C32-54 and proinsulin24-36 (r=0.82, P<0.0001), coxsackie P2-C32-54 and GAD506-518 (r=0.82, P<0.0001), and GAD254-276 and proinsulin24-36 (r=0.83, P<0.0001). Strikingly, increased responses to peptides were found almost exclusively in subjects with high stimulation indices against the recall antigen tetanus toxoid, further suggesting that peripheral blood T cell responses are related to a general subject hyperreactivity. These data suggest that proliferative T cell responses to peptides containing putative autoreactive epitopes of GAD65 and proinsulin are not specific for type 1 diabetes, that correlation between T cell reactivity to peptides is not restricted to those containing homologous regions, and that non-antigen-specific factors are important determinants of in vitro measurements of T cell reactivity.
Na+,K+-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extra cellular fluid. Its activity is decreased in many tissues of streptozotocin-induced diabetic animals. This impairment could be at least partly responsible for the development of diabetic complications. Na+,K+-ATPase activity is decreased in the red blood cell membranes of type 1 diabetic individuals, irrespective of the degree of diabetic control. It is less impaired or even normal in type 2 diabetic patients. It is said that in the red blood cells of type 2 diabetic patients, Na+,K+-ATPase activity was strongly related to blood C-peptide levels in non-insulin-treated patients (in whom C-peptide concentration reflects that of insulin) as well as in insulin-treated patients.
Furthermore, a gene-environment relationship has been observed.
The alpha-1 isoform of the enzyme predominant in red blood cells and nerve tissue are encoded by the ATP1A1 gene. Apolymorphism in the intron 1 of this gene is associated with lower enzyme activity in patients with C-peptide deficiency either with type 1 or type 2 diabetes, but not in normal individuals. There are several evidence for a low C-peptide level being responsible for low Na+,K+-ATPase activity in the red blood cells. Short-term C-peptide infusion to type 1 diabetic patients restores normal Na+,K+-ATPase activity. Islet transplantation, which restores endogenous C-peptide secretion, enhances Na+, K+-ATPase activity proportionally to the rise in C-peptide. This C-peptide effect is not indirect. In fact, incubation of diabetic red blood cells with C-peptide at physiological concentration leads to an increase in Na+, K+-ATPase activity. In isolated proximal tubules of rats or in medullary thick ascending limb of the kidney, C-peptide stimulates Na+, K+-ATPase activity in a dose-dependent manner. This impairment in Na+, K+-ATPase activity, mainly secondary to the lack of C-peptide, plays a role in the development of diabetic complications.
Arguments have been developed showing that the diabetes induced decrease in Na+,K+-ATPase activity compromises microvascular blood flow by two mechanisms:
"By affecting microvascular regulation
"By decreasing red blood cell deformability, which leads to an increase in blood viscosity
C-peptide infusion restores red blood cell deformability and microvascular blood flow concomitantly with Na+,K+-ATPase activity. The defect in ATPase is strongly related to diabetic neuropathy. Patients with neuropathy have lower ATPase activity than those without. The diabetes-induced impairment in Na+,K+-ATPase activity is identical in red blood cells and neural tissue. Red blood cell ATPase activity is related to nerve conduction velocity in the peroneal and the tibial nerve of diabetic patients. C-peptide infusion to diabetic rats increases endoneural ATPase activity in rat. Because the defect in Na+,K+-ATPase activity is also probably involved in the development of diabetic nephropathy and cardiomyopathy, physiological C-peptide infusion could be beneficial for the prevention of diabetic complications.
Recently, Casper G. Schalkwijk (VU University Medical Center, Netherlands), Piet M. Ter Weeb and Coen D. A. Stehouwerc (University Hospital Maastricht, Netherlands) have found that patients with renal impairment have an increased risk for cardiovascular disease, which may be the result of advanced glycation end products (AGEs). The aim of the study was to investigate the levels of AGE peptides in relation to kidney function and to study the relationship of AGE peptides with endothelial function and inflammation in type 1 diabetic patients. They measured plasma levels of AGE peptides with a simple fluorescent analytical procedure in patients with end-stage renal disease with or without diabetes and in 60 type 1 diabetic patients categorized as having normo-, micro-, or macroalbuminuria.
Using enzyme-linked immunosorbent assays, they determined vascular cell adhesion molecule 1 (sVCAM-1), sE-selectin, plasminogen activator inhibitor 1 (PAI-1), tissue type-specific plasminogen activator (tPA), von willebrand factor (vWF) and soluble thrombomodulin (sTM) to be markers of endothelial function and determined C-reactive protein (CRP) to be a marker of inflammation. AGE peptides were increased approximately fivefold in patients with end-stage renal disease, without difference between patients with or without diabetes. In type 1 diabetic patients the increase of AGE peptides across the groups normo-, micro- and macroalbuminuria (with medians [range] of 12.6% [7.8-27.2%], 12.1% [7.8-162%], and 46.5% [9.0-248.9%]) was associated with serum creatinine level and not with albumin excretion rate (AER). The relationship with serum creatinine decreased but remained significant after adjusting for age, sex, diabetes duration, haemoglobin A1c (HbA1c), AER, systolic and diastolic blood pressure (BP) and CRP in multiple linear-regression analysis. AGE peptide levels were significantly associated with sVCAM-1 and sTM, independently of serum creatinine. However, these relationships are no longer significant after adjusting for age, sex, diabetes duration, HbA1c, AER, systolic and diastolic BP and CRP. This study shows that plasma levels of AGE peptides rise with renal impairment, as determined by serum creatinine. AGE peptides are associated with some markers of endothelial activation, which may suggest an involvement of AGE peptides in the acceleration of cardiovascular complications in type 1 diabetic patients with renal impairment.
(The author is a specialist in chemicals and pharmaceuticals based in Mumbai.)