Physiological background. What is C-peptide?

In healthy individuals

Pancreatic beta-cells produce proinsulin
Proinsulin split into C-peptide and insulin
C-peptide and insulin are released into circulation

In Type 1 diabetes patients
Pancreatic beta-cells cease to function
No proinsulin is produced
Neither insulin nor C-peptide are formed

Patients are treated with replacement insulin, but does not receive C-peptide.
Long-term complications of diabetes frequently develop despite insulin therapy and optimal blood glucose control

The major long-term complications in Type 1 diabetes are:

Nephropathy, resulting in gradual loss of kidney function, occurs in 20-30% of the patients after 15-20 years.
Neuropathy, resulting in reduced sensibility of the feet and lower legs, ulcer formation, gastrointestinal and sexual dysfunction, occurs in 30-50% of the patients after 15-20 years.
Retinopathy, resulting in retinal edema, hemorrhage and loss of vision, occurs in 40-60% of the patients after 15-20 years.
Cellular effects of C-peptide

C-peptide binds to a receptor at the cell surface and activates signal transduction pathways that result in stimulation of and endothelial nitric oxide synthase (eNOS), both of which are enzymes with reduced activitities in diabetes.
C-peptide replacement therapy: proof of efficiency in rats-Treatment effective even after long-term disease progression

Nerve conduction velocity (NCV) in diabetic and healthy control rats during treatment with C-peptide or placebo. The progressive decline seen in placebo treated animals was arrested when
C-peptide treatment started one week after onset of diabetes. The NCV increased significantly when C-peptide was administered at 5 months after onset of diabetes (red symbols)
Diabetic peripheral neuropathy sensory nerve improvement after 3 months of C-peptide replacement

Sensory nerve dysfunction in patients with peripheral neuropathy, typically involve the feet and the lower legs and the hands. In a 3 month, randomized, double-blind, placebo-controlled clinical trial, following C-peptide treatment sensibility impairment regresses but returns 3 months after treatment. In a subsequent randomized, double-blind, placebo-controlled clinical trial, sensibility impairment significantly regressed after 6 month replacement therapy with C-peptide.
Summary of clinical effects

C-peptide replacement in Type 1 diabetes

Improves sensory nerve dysfunction and structural abnormalities (increased SNCV, vibration perception, regression of nodal changes, increased axonal regeneration) and improves autonomic nerve function (heart rate variability)
Improves renal dysfunction (normalized glomerular filtration, decreased albumin excretion) and reduces diabetes-induced structural changes (decreases mesangial expansion)
Increases regional blood flow (muscle, myocardium, nerve and kidney)
C-peptide development project, status

Clinical studies in more than 400 type 1 diabetes patients have demonstrated encouraging nerve and kidney efficacy data with no observed C-peptide related adverse reactions
Positive results in a recently completed phase II trial in >160 type 1 diabetes patients with peripheral neuropathy
Pre-clinical and phase 1 regulatory packages approved by the Swedish Medical Products Agency
Production process ready for scale up
Formulation studies for once daily administration in progress
A broad patent portfolio has been filed; two applications have been granted in the US and other countries
Molecular and cellular actions of C peptide documented from extensive studies in different in vitro and in vivo models