Complications of diabetes
The incidence and the risk of type-1 diabetes differs between populations with highest rates reported for Finland (> 30 cases per year and 100,000 inhabitants), and minimal rates for developing countries (< 2). The incidence rates in central Europe vary between 5.2 and 12.1. A census from the early 80's reported 7.4 cases per year and 100,000 for Germany . It has long been expected that the level and duration of high blood glucose (hyperglycemia) is strongly associated with a variety of microvascular complications, such as eye, kidney, and nerve disease.
The Diabetes Control and Complications Trial (DCCT), a randomised trial included a total of 1,441 patients with type-1 diabetes and was published in 1993. The DCCT for the first time provided unequivocal evidence that, in fact, lower blood glucose concentrations delay the onset of diabetic complications . Subjects chosen for the primary prevention cohort had had diabetes for 1–5 years with no evidence of eye disease or initial kidney disease. The biological parameters used in this study have become important for studies on patients with type-1 diabetes, in general. Glycemic control was assessed with glycosylated hemoglobin (GHb). GHb is widely used in diabetes studies to describe the mean blood glucose level over a period of 4–6 weeks. Eye disease is diagnosed by fundus examination, and nerve disease is assessed by testing the vibration threshold of the foot. Measurement of albumine in the urine is a screening method to detect diabetic kidney disease at an early stage.
Residual Beta Cell Function
A few months after the initiation of insulin therapy endogeneous insulin production recovers. Disease remission is characterised by a significant reduction of therapeutic insulin, sometimes patients are even completely "off insulin". Although insulin therapy has been practiced by physicians for decades, it is hypothesized that only modern insulin therapy has the potential to maintain a significant insulin reserve over a longer period of time mainly by reducing the glucotoxic effect on the pancreatic cells.
Treatment with immunosuppressive drugs to protect insulin producing cells from the immune attack showed that initial improvement did not last longer compared to insulin injection alone. These studies used plasma C-peptide concentration for the measurement of insulin reserve because it is secreted in equimolar amounts with endogeneous insulin. The C-peptide radioimmunoassay did not crossreact with injected insulin circulating in the blood stream. It was also found that adult-onset patients with type-1 diabetes have a longer period of residual insulin secretion than children .
Recently, intrinsic biological acitivity of C-peptide was described after years of general belief, that it is not biologically active .
A subgroup of 303 participants of the DCCT trial who were diagnosed for diabetes less than five years from baseline had a positive endogeneous insulin response. These patients were reported to have a lower value of mean blood glucose as GHb and also a 50% reduced risk for progression of eye disease .
It was also observed that hypoglycemia (low blood glucose concentration) – a typical side effect of the subcutaneous injection of insulin – occurred less frequently in patients with residual C-Peptide .
Conventional and Intensive Insulin Therapy
The majority of patients face a challenge when the goal is optimal regulation of blood glucose. Indeed, only 5% of patients in the DCCT, a carefully selected and closely monitored group, maintained glycosylated hemoglobin levels in the normal, nondiabetic range through the whole trial. Optimal diabetes care is a behavioral, psychosocial and motivational challenge for caregivers and patients. Therefore, the term "intensive" insulin therapy describes a comprehensive approach to the goal of optimal glycemia. In principle, different educational strategies have been developed to teach patients how to increase the number of insulin injections and frequency of testing. The "intensive" strategy also includes a systematic approach to quantifying food and matching insulin to food intake, and education that enables patients to change aspects of the regimen for varying circumstances. By contrast, "conventional" therapy is a less complex and demanding regimen concerning the performance of several unpleasant tasks: injections (not more than three per day), testing, dietary modifications, and exercise routines.
Hypoglycemia is the principal adverse effect of intensive diabetes management. Fear of hypoglycemia is an important determinant of patients' personal goals for glycemic control. In the DCCT, intensively managed patients had three times as many episodes of severe hypoglycemia as their conventionally treated peers.
In Germany, intensive insulin therapy has become standard in the past 10 years, 8 out of 10 subjects with long standing insulin-dependent diabetes practice this kind of therapy . Most care providers feel, that intensive therapy should be implemented from the first day of diagnosis, because they have the impression that quality of life of the patient is superior compared to conventional therapy.
A pilot trial conducted at our department on 49 adult type-1 diabetic patients with persisting insulin reserve and randomised for either intensive or conventional therapy resulted in reduced prevalence of peripheral neuropathy in the intensively treated group .
Although C-peptide was measured in some patients of the DCCT we must express our concerns on the validity of these data, since insulin reserve was not the main objective of the DCCT. A bulk of uncontrolled trials in the past 20 years has implicated that residual C-peptide was beneficial for the prevention of diabetes related vascular disease. This is an important reason for the conduction of this trial. Further, intensive insulin therapy was thought to be the optimal way for glucose control in type-1 diabetes, however only a minority of patients comply with all the elements necessary for optimal control over a time period of several years. Therefore we think that our trial will help to settle the question whether preservation of residual insulin/C-peptide facilitates stabile glucose levels. Moreover, intensive insulin therapy is considered optimal for all patients, however a major obstacle is the increased incidence of severe hypoglycemia. We had observed in the pilot trial that patients with residual insulin on intensive therapy had no episode of severe hypoglycemia (defined as the need of intravenous injection of glucose).
Since 1998 we planned a prospective randomised trial to document the advantage of intensive insulin therapy in the preservation of insulin reserve and also the protection from complications by residual insulin in type-1 diabetes. This would require a large sample size, which could only be realized by a multicenter trial. Furthermore, such a study would have to recognize aspects of self-management, life quality, training, psychosocial factors, and coping strategies of the patient.
To begin with we performed a telephone survey in twenty clinical diabetes centers in Germany. It became clear that the access of a sufficient number of patients to such a trial would require the collaboration of several centres and years of cooperative data collection.
Aims and objectives
The DCCT landmark study for the treatment of insulin dependent diabetes demonstrated that reduction of hyperglycemia was associated with prevention of microvascular complications. But there still remained several open issues .
Will intensive therapy delay the breakdown of patients' own remaining insulin output in contrast to conventional therapy?
Will intensive therapy improve glucose control and delay or prevent the development of long-term complications?
Which factors determine the preservation of C-peptide concentration when diabetes proceeds with time?
The NeuDia Trial is a national multicenter open controlled randomised study. Four clinic-based diabetes centres in Germany participate in the recruitment process. The protocol was approved by the responsible institutional review boards. Each recruited subject has to sign an informed consent form. Patients give their consent to randomisation and/or collection of data depending if they enter randomisation or the observational follow-up.
Interventional cohorts will be instructed to practice basis-bolus (intensive) insulin therapy. This therapy includes frequent injections at meal times with variable doses of short-acting insulins, estimation of carbohydrate content of the meals, self-dosage of insulins, self-management of insulin requirement. The participating centres have agreed on the detailed algorithms of this intervention.
Control (conventional) groups will apply not more than three insulin injections per day without making allowance for different meal sizes or flexible insulin dosage adaptions apart from ambient blood glucose.
Study population, inclusion and exclusion criteria
Subjects are recruited from diabetic patients diagnosed with type-1 diabetes not more than three months ago. Type-1 diabetes is defined by more than one elevated blood glucose (concentration >11.1 mmol/l), and the medical decision to prescribe insulin within three months after diagnosis. The frequency of antibodies indicating an autoimmune process is expected to be less than 50% in adult type-1 diabetes [10, 11]. Therefore the presence of diabetes related antibodies may support diagnosis but will be not mandatory for incusion.
Men or women aged 18–40 years at diagnosis
Established Type-1 Diabetes diagnosed up to three months ago
Consent to participate in a diabetes training programme
Informed consent before enrollment
History of neuropathy, nephropathy, and retinopathy of other than diabetes related origin
Negative C-peptide level at diagnosis
History of psychiatric disease or drug or alc ohol abuse
Treatment with oral antidiabetic medication
Subject unlikely to comply with the protocol (e.g. inability or unwillingness to participate adequate training or to complete diaries appropriately) or to understand the nature and the scope of the study
Subsequent eligible patients and their status concerning the study are recorded. Additionally, the number of those patients refusing data collection are recorded in each centre.
Compliance of patients after inclusion
A patient is considered non-compliant when he/she:
- misses more than two visits without contacting the study centre
- moves and does not provide a new address or phone number
- Wants to change therapy due to personal reasons