Use of gp130 activators in diabetic neuropathy

The present invention is in the field of diabetes mellitus and peripheral nervous system disorders. In particular, it relates to the use of substances signaling through gp130 for the manufacture of a medicament for the treatment and/or prevention of diabetic neuropathy. IL-6, or an IL-6R/IL-6 chimera are preferably used in this specific medical indication.

Diabetes mellitus is a disorder of carbohydrate metabolism, i.e. a syndrome characterized by hyperglycemia resulting from absolute or relative impairment in insulin secretion and/or insulin action.

Classification of Diabetes mellitus is based on the one adopted by the National Diabetes Data Group and WHO. Previously, it was based on age at onset, duration, and complications of the disease. Gestational diabetes mellitus is carbohydrate intolerance of variable severity with onset or first recognition during the current pregnancy. Patients with type I diabetes mellitus (DM), also known as insulin-dependent DM (IDDM) or juvenile-onset diabetes, may develop diabetic ketoacidosis (DKA). Patients with type II DM, also known as non-insulin-dependent DM (NIDDM), may develop nonketotic hyperglycemic-hyperosmolar coma (NKHHC). Common late microvascular complications include retinopathy, nephropathy, and peripheral and autonomic neuropathies. Macrovascular complications include atherosclerotic coronary and peripheral arterial disease.

Type I diabetes mellitus: Although it may occur at any age, type I diabetes mellitus most commonly develops in childhood or adolescence and is the predominant type of DM diagnosed before age 30. This type of diabetes accounts for 10 to 15% of all cases of DM and is characterized clinically by hyperglycemia and a propensity to diabetic ketoacidosis. The pancreas produces little or no insulin.

About 80% of patients with type I DM have specific HLA phenotypes associated with detectable serum islet cell cytoplasmic antibodies and islet cell surface antibodies (antibodies to glutamic acid decarboxylase and to insulin are found in a similar proportion of cases).

In these patients, type I DM results from a genetically susceptible, immune-mediated, selective destruction of >90% of their insulin-secreting cells. Their pancreatic islets exhibit insulitis, which is characterized by an infiltration of T lymphocytes accompanied by macrophages and B lymphocytes and by the loss of most of the beta-cells, without involvement of the glucagon-secreting alpha-cells. The antibodies present at diagnosis usually become undetectable after a few years. They may be primarily a response to beta-cell destruction, but some are cytotoxic for beta-cells and may contribute to their loss. The clinical onset of type I DM may occur in some patients years after the insidious onset of the underlying autoimmune process. Screening for these antibodies is included in numerous ongoing preventive studies.

Type II diabetes mellitus: Type II DM is usually the type of diabetes diagnosed in patients >30 years, but it also occurs in children and adolescents. It is characterized clinically by hyperglycemia and insulin resistance. Diabetic ketoacidosis is rare. Although most patients are treated with diet, exercise, and oral drugs, some patients intermittently or persistently require insulin to control symptomatic hyperglycemia and prevent nonketotic hyperglycemic-hyperosmolar coma. The concordance rate for type II DM in monozygotic twins is >90%. Type II DM is commonly associated with obesity, especially of the upper body (visceral/abdominal), and often present after a period of weight gain. Impaired glucose tolerance associated with aging is closely correlated with the typical weight gain. Type II DM patients with visceral/abdominal obesity may have normal glucose levels after losing weight.

Type II DM is a heterogeneous group of disorders in which hyperglycemia results from both an impaired insulin secretory response to glucose and decreased insulin effectiveness in stimulating glucose uptake by skeletal muscle and in restraining hepatic glucose production (insulin resistance). However, insulin resistance is common, and most patients with insulin resistance will not develop diabetes, because the body compensates by adequately increasing insulin secretion. Insulin resistance in the common variety of type II DM is not the result of genetic alterations in the insulin receptor or the glucose transporter. However, genetically determined post-receptor intracellular defects likely play a role. The resulting hyperinsulinemia may lead to other common conditions, such as obesity (abdominal), hypertension, hyperlipidemia, and coronary artery disease (the syndrome of insulin resistance).

Genetic factors appear to be the major determinants for the development of type TI DM, yet no association between type II DM and specific HLA phenotypes or islet cell cytoplasmic antibodies has been demonstrated. An exception is a subset of non-obese adults with detectable islet cell cytoplasmic antibodies who carry one of the HLA phenotypes and who may eventually develop type I DM.

Before diabetes develops, patients generally lose the early insulin secretory response to glucose and may secrete relatively large amounts of proinsulin. In established diabetes, although fasting plasma insulin levels may be normal or even increased in type II DM patients, glucose-stimulated insulin secretion is clearly decreased. The decreased insulin levels reduce insulin-mediated glucose uptake and fail to restrain hepatic glucose production.

Hyperglycemia may not only be a consequence but also a cause of further impairment in glucose tolerance in the diabetic patient (glucose toxicity) because hyperglycemia decreases insulin sensitivity and increases hepatic glucose production. Once a patient\'s metabolic control improves the insulin or hypoglycemic drug dose is usually lowered.

Some cases of type II DM occur in young, non-obese adolescents (maturity-onset diabetes of the young [MODY]) with an autosomal dominant inheritance. Many families with MODY have a mutation in the glucokinase gene. Impairments in insulin secretion and in hepatic glucose regulation have been demonstrated in these patients.

Insulinopathies are rare cases of DM, with the clinical characteristics of type II DM, result from the heterozygous inheritance of a defective gene, leading to secretion of insulin that does not bind normally to the insulin receptor. These patients have greatly elevated plasma immunoreactive insulin levels associated with normal plasma glucose responses to exogenous insulin.

Diabetes may also be attributed to pancreatic disease: Chronic pancreatitis, particularly in alcoholics, is frequently associated with diabetes. Such patients lose both insulin-secreting and glucagon-secreting islets. Therefore, they may be mildly hyperglycemic and sensitive to low doses of insulin. Given the lack of effective counterregulation (exogenous insulin that is unopposed by glucagon), they frequently suffer from rapid onset of hypoglycemia. In Asia, Africa, and the Caribbean, DM is commonly observed in young, severely malnourished patients with severe protein deficiency and pancreatic disease; these patients are not prone to diabetic ketoacidosis but may require insulin.

Diagnosis of diabetes mellitus: In asymptomatic patients, DM is established when the diagnostic criterion for fasting hyperglycemia is met: a plasma (or serum) glucose level of >=140 mg/dl (>=7.77 mmol/l) after an overnight fast on two occasions in an adult or child.

An oral glucose tolerance test may be helpful in diagnosing type II DM in patients whose fasting glucose is between 115 and 140 mg/dl (6.38 and 7.77 mmol/L) and in those with a clinical condition that might be related to undiagnosed DM (e.g. polyneuropathy, retinopathy).

Treatment of diabetes mellitus: Hyperglycemia is responsible for most of the long-term microvascular complications of diabetes. It demonstrated a linear relationship between the levels of Hb A_1c (see below) and the rate at which complications developed. Other studies have suggested that Hb A_1c<8% is a threshold below which most complications can be prevented. Thus, therapy for type I DM should try to intensify metabolic control to lower Hb A_1c while avoiding hypoglycemic episodes. However, treatment must be individualized and should be modified when circumstances make any risk of hypoglycemia unacceptable (e.g. in patients with a short life expectancy and in those with cerebrovascular or cardiac disease) or when the patient\'s risk of hypoglycemia is increased (e.g. in patients who are unreliable or who have autonomic neuropathy).

Diet to achieve weight reduction is most important in overweight patients with type II DM. If improvement in hyperglycemia is not achieved by diet, trial with an oral drug should be started.

The patient should be regularly assessed for symptoms or signs of complications, including a check of feet and pulses and sensation in the feet and legs, and a urine test for albumin. Periodic laboratory evaluation includes lipid profile, BUN (blood urea nitrogen) and serum creatinine levels, ECG, and an annual complete opthalmologic evaluation.

Hypercholesterolemia or hypertension increases the risks for specific late complications and requires special attention and appropriate treatment. Although beta-adrenergic receptor blocking agents β-blockers, such as propranolol) can be used safely in most diabetics, they can mask the β-adrenergic symptoms of insulin-induced hypoglycemia and can impair the normal counterregulatory response. Thus, ACE inhibitors and calcium antagonists are often the drugs of choice.

Plasma glucose monitoring should be carried out by all patients, and insulin-treated patients should be taught to adjust their insulin doses accordingly. Glucose levels can be tested with easy-to-use home analyzers using a drop of fingertip blood. A spring-powered lancet is recommended to obtain the fingertip blood sample. The frequency of testing is determined individually. Insulin-treated diabetic patients ideally should test their plasma glucose daily before meals, 1 to 2 hours after meals, and at bedtime.