Insulin C-peptides

Details Insulin C-peptides Insulin C-peptides

1999-07-08

2003-08-26

Celsa, Bennett (Department: 1639)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C514S016700, C514S017400, C514S018700, C530S324000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06610649

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to fragments of the insulin C-peptide and their use in the treatment of diabetes and diabetic complications.
BACKGROUND
Patients with insulin-dependent diabetes mellitus (IDDM), generally synonymous with type 1 diabetes, cannot survive without insulin therapy. IDDM is the classical, life-threatening form of diabetes, the treatment of which was revolutionized by the discovery of insulin in 1922. The prevalence of IDDM in Europe, North America and Japan is 0.25-0.4% of the population. There is a seasonal variation in the incidence of IDDM with more patients presenting in the autumn and winter months. The disorder affects a slight excess of males but this difference becomes less marked with increasing age.
The classical symptoms of IDDM in its acute phase are thirst, large urine volumes, fatigue and weight loss. Less frequent and minor symptoms are muscle cramps, skin infections and blurred vision. Nausea and vomiting may occur in advanced stages and denote impending ketoacidosis and coma. The duration of symptoms is short, usually 2-3 weeks or less. The patients present with high concentrations of glucose and ketone bodies in blood and urine while insulin levels are low or undetectable.
The etiology of IDDM is multifactorial but most likely includes a genetic predisposition for autoimmune reactivity together with environmental triggering, possibly via a virus infection, resulting in partial or complete destruction of the pancreatic beta cells. The destruction of beta cells may have been in progress during the 6-12 months preceding the onset of the disorder. In the acute phase of IDDM insulin deficiency is thus the dominating pathophysiological feature.
After starting insulin treatment many patients enjoy good blood glucose control with only small doses of insulin. There is an early phase, the “honeymoon period”, which may last a few months to a year and which probably reflects a partial recovery of beta cell function. This is, however, a temporary stage and ultimately, the progressive autoimmune destruction of the beta cells leads to increasing requirements for exogenous insulin.
While the short term effects of hypoinsulinemia in the acute phase of IDDM can be well controlled by insulin administration, the long term natural history of IDDM is darkened by the appearance in many patients of potentially serious complications. These include the specifically diabetic problems of nephropathy, retinopathy and neuropathy. These conditions are often referred to as microvascular complications even though microvascular alterations are not the only cause. Atherosclerotic disease of the large arteries, particularly the coronary arteries and the arteries of the lower extremities, may also occur.
Nephropathy develops in approximately 35% of IDDM patients particularly in male patients and in those with onset of the disease before the age of 15 years. The diabetic nephropathy is characterized by persistent albuminuria secondary to glomerular capillary damage, a progressive reduction of the glomerular filtration rate and eventually, end stage renal failure.
The prevalence of diabetic retinopathy is highest among young-onset IDDM patients and it increases with the duration of the disease. Proliferative retinopathy is generally present in about 25% of the patients after 15 years duration and in over 50% after 20 years. The earliest lesion of diabetic retinopathy is a thickening of the capillary basement membrane, there is then capillary dilatation and leakage and formation of microaneurysms. Subsequently, occlusion of retinal vessels occurs resulting in hypoperfusion of parts of the retina, oedema, bleeding and formation of new vessels as well as progressive loss of vision.
Diabetic neuropathy includes a wide variety of disturbances of somatic and autonomic nervous function. Sensory neuropathy may cause progressive loss of sensation or, alternatively, result in unpleasant sensations, often pain, in the legs or feet. Motor neuropathy is usually accompanied by muscle wasting and weakness. Nerve biopsies generally show axonal degeneration, demyelination and abnormalities of the vasa nervorum. Neurophysiological studies indicate reduced motor and sensory nerve conduction velocities. Autonomic neuropathy afflicts some 40% of the patients with IDDM of more than 15 years duration. It may evolve through defects in thermoregulation, impotence and bladder dysfunction followed by cardiovascular reflex abnormalities. Late manifestations may include generalized sweating disorders, postural hypotension, gastrointestinal problems and reduced awareness of hypoglycemia. The latter symptom has grave clinical implications.
Several theories have been advanced with regard to possible mechanism(s) involved in the pathogenesis of the different diabetic complications (1). Metabolic factors may be of importance and recent studies demonstrate that good metabolic control is accompanied by significantly reduced incidence of complications of all types (2). Nevertheless, after 7-10 years of good metabolic control as many as 15-25% of the patients show signs of beginning nephropathy, 10-25% have symptoms of retinopathy and 15-20% show delayed nerve conduction velocity indicating neuropathy. With longer duration of the disease the incidence of complications increases further.
C-peptide is a part of the proinsulin molecule which, in turn, is a precursor to insulin formed in the beta cells of the pancreas. Human C-peptide is a 31 amino acid peptide having the following sequence: EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ (SED ID. NO. 1). It has been suggested in EP 132 769 that C-peptide may be given for the treatment of diabetes and in SE 460334 that insulin in combination with C-peptide can be administered in the treatment of diabetes and in the prevention of diabetic complications.
In recent years it has become apparent that type 1 diabetes is accompanied by consistently reduced activity of the enzyme Na
+
K
+
ATPase in several tissues, notably in renal glomeruli, retina, peripheral nerve, heart and skeletal muscle (3, 4, 5). Na
+
K
+
ATPase is an enzyme that is localized to the cell membrane and generates energy for transcellular transport of Na
+
and K
+
as well as for all co- or countertransported substrates in all mammalian cells. It is thus obvious that the activity of this enzyme is of fundamental importance for normal cell function. Deficient Na
+
K
+
ATPase activity in nervous tissue, glomeruli and retina is likely to be an important contributing factor in the pathogenesis of diabetic neuropathy, nephropathy and retinopathy. Na
+
K
+
ATPase activity is regulated via the Na
+
concentration and by hormonal action; several hormones stimulate (thyroid hormone, noradrenalin, angiotensin, neuropeptide Y, insulin) or inhibit (dopamine, ANF) the enzyme's activity (6). Despite insulin treatment sufficient to achieve good glycemic control, patients with type 1 diabetes show signs of insufficient Na
+
K
+
ATPase activity on a long term basis.
BRIEF SUMMARY OF THE INVENTION
The present invention is based on the discovery of a group of peptides from the middle portion and the C-terminal part of the C-peptide molecule which are characterized by a remarkable ability to stimulate Na
+
K
+
ATPase activity. These peptides are all small fragments of the C-peptide molecule. C-peptide itself is able to stimulate Na
+
K
+
ATPase via activation of a G-protein, increase in the intracellular Ca
2+
concentration and activation of protein phosphatase 2B (7). However, the smaller peptides' stimulatory effect on Na
+
K
+
ATPase activity is similar to or greater than that of C-peptide itself. There is both in vitro and in vivo evidence to indicate that upon administration of one of these peptides together with regular insulin treatment, renal function improves, early signs of retinopathy regress and the function of somatic and autonomic nerves improves. Treatment with these specific peptides, opt

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