Evaluación de la capacidad antagónica de los hongos Trichoderma spp Y

Hyperproinsulinaemia is a common feature in subjects with impaired glucose tolerance (IGT), non-insulin-dependent diabetes mellitus (NIDDM), gestational diabetes and insulinomas. Increased proinsulin secretion has also been found in subjects with insulin dependant diabetes mellitus (IDDM) (Ludvigsson and Heding, 1982; Heding et al, 1981) and in other clinical states associated with glucose intolerance, such as cystic fibrosis (Hartling et al, 1988), and hypokalemia (Gorden et al, 1972). More recent data has shown that hyperproinsulinaemia is associated with increased cardiovascular risk.

1.7.1 Hyperproinsulinaemia in IGT and NIDDM

The true insulin status of subjects with NIDDM is often unclear, leading to confusion as to whether they are hypo- or hyperinsulinaemic. Evidence from epidemiological data suggests that there is an increase in plasma insulin levels as glucose intolerance increases until the subject is frankly hyperglycaemic, at which time insulin levels fall (Zimmet et al, 1990). Studies on jS-cell function have implied an impairment of insulin secretion. There are several reasons for this confusion.

Firstly, the assessment of insulin secretion is difficult. Peripheral insulin

levels are assumed to reflect in vivo insulin release, when it has been shown that the hepatic extraction and peripheral clearance of insulin are not constant (Ferrannini et al, 1983). Though methods for calculating insulin secretion rates using mathematical models (Stuns et al, 1991) and C-peptide infusion rate (Shapiro et al, 1988) exist, these have not been widely used. Secondly, the insulin response is related to the magnitude of the jS-cell stimulus applied. It has been shown that at an initial blood glucose range modest increases in the oral glucose load, raising plasma level by as little as 1 mmol/1, is adequate to increase the insulin response by 50-70% (Cerasi et al, 1973). This suggests that even if the insulin levels in a hyperglycaemic subject are similar to those of one with normoglycaemia, this may actually indicate impaired insulin secretion.

The third problem is the nature of the antigen measured by immunoassays employed in various studies. It has been shown that, even under relatively mild hyperglycaemic conditions, the proportion of circulating proinsulin rises from being less than 10% to 15-20% (Yoshioka et al, 1988), and being greater than 40% when severe hyperglycaemia occurs (Leahy, 1990; Yoshioka et al, 1988). Hyperproinsulinaemia has also been observed in subjects with normoglycaemia but with islet cell dysfunction (Porte and Kahn, 1989; Hartling et al, 1989). In the face of these changes in the proportion of circulating proinsulin-like molecules it is imperative that studies use specific assays for insulin or assays with clearly defined degrees of cross-reactivity. Some assays have used antibodies with greater than 60% cross reactivity to the insulin-like molecules.

More recently several studies have been published employing specific measures of insulin and proinsulin. In one study of subjects with NIDDM approximately 50% of all insulin-like molecules in the fasting state consisted of proinsulin and des 31,32 proinsulin (Temple et al, 1989). They reported, following a 75g oral glucose load, a loss in first phase insulin release in subjects with NIDDM. These data may explain the confusion concerning the

relative contributions of insulin resistance and insulin deficiency to the aetiology of NIDDM and suggest it may result from misinterpretation of the contribution of hyperproinsulinaemia to hyperinsulinaemia. The data show, however, that although insulin deficiency is a feature of NIDDM it cannot wholly explain the hyperglycaemia in this condition.

Another study used a specific insulin assay and a mathematical model based on fasting concentrations of insulin and glucose to determine the contribution of insulin deficiency and resistance to the aetiology of NIDDM (Nagi et al, 1990). This study showed a significantly greater contribution of insulin deficiency than of insulin resistance to the degree of hyperglycaemia. In the 51 subjects studied the proinsulin-like molecules accounted for approximately 60% of the total immunoreactive insulin, although in other reports this proportion has generally been around 30% (Yoshioka et al, 1988).

Several groups have reported the effects of hypoglycaemic therapy on concentrations of proinsulin-like molecules in subjects with NIDDM. Diet- treated subjects who had an accompanying weight reduction had lower levels of circulating proinsulin and insulin but the relative proportion of proinsulin to insulin was not significantly decreased (Yoshioka et al, 1989). Chlorpropamide treatment produced increases in both the absolute and relative proinsulin concentration (Elkeles et al, 1982). A randomised, cross-over study of 11 subjects with NIDDM assessed the effects of insulin and sulphonylurea treatment on the levels of proinsulin-like molecules (Jain et al, 1993). While glycaemic control was not altered by either therapy, insulin produced reductions of 43 and 20% in the concentrations of intact proinsulin and des 31, 32 proinsulin.

Currently, the cause of hyperproinsulinaemia in NIDDM is thought to be a pancreatic jS-cell defect that is augmented by the increased demand placed on jS-cell by hyperglycaemia, rather than a decreased clearance of proinsulin-like molecules from the circulation (Temple et al, 1989). A /(3-cell defect could be

represent, either a primary dysfunction of the conversion mechanism itself, or a malfunction in related jS-cell regulatory mechanisms that affect insulin production secondary to hyperglycaemia. Recent advances have led to a clearer understanding of the mechanisms and regulation of proinsulin processing and certain defects in the proinsulin conversion mechanism may contribute to hyperproinsulinaemia.

1.7.2 Hyperproinsulinaemia in gestational diabetes

Gestational diabetes refers to glucose intolerance occurring in pregnancy, which abates following delivery, usually to recur as impaired glucose tolerance or NIDDM over the next decades (O’Sullivan, 1982; Domhorst et al, 1990). It is encountered in 2-3% of all pregnancies (Hadden, 1985). Several studies have shown that women both with gestational diabetes and with previous gestational diabetes have abnormalities in insulin response to glucose, with raised levels of circulating proinsulin and proinsulin-like molecules as well as insulin resistance (Ward et al, 1985; Efendic et al, 1987, Persson et al, 1985). Elevated proinsulin levels have been demonstrated in gestational diabetic subjects with normal fasting plasma glucose levels (Domhorst et al, 1991). These results appear to suggest a primary defect in proinsulin processing or insulin secretion.

1.7.3 Hyperproinsulinaemia in insulinoma

The majority of patients with benign or malignant insulinoma have both raised relative and absolute levels of circulating proinsulin-like molecules (Lazarus et al, 1970; Gutman et al, 1971). Delayed peripheral clearance of proinsulin as the sole cause of the high plasma levels was deemed unlikely since there were abnormally large amounts of proinsulin-like material in the tumour itself (Rastogi et al, 1973). In a study of patients with both benign and malignant insulinomas proinsulin-like molecules accounted for 8-78% of total serum immunoreactive insulin, with amounts abnormally increased in over 70% of those studied (Sherman et al, 1972). In insulinoma patients with a normal range of immunoreactive insulin proinsulin-like materials have been shown to

account for 66% of it (Alsever et al, 1975). Several factors may account for the hyperproinsulinaemia characteristic of patients with insulinoma, such as an increased rate of proinsulin synthesis, defective conversion, storage and release mechanisms, production of a defective peptide, or a combination of these events. Data from in vitro studies of insulinoma tissues suggests that marked shortening of storage and processing phases result in defective conversion of proinsulin to insulin (Creutzfeldt et al, 1973). The tumours produced proinsulin at an overall rate similar to that in normal, isolated pancreatic islets. However, a shortened storage phase allowed secretion before adequate proinsulin processing had occurred. The cause of this accelerated release and a shortened storage is unclear, but, perhaps suggests shunting to the constitutive pathway.

1.7.4 Proinsulin-like molecules and cardiovascular risk factors

Subjects with NIDDM have a substantially elevated risk of cardiovascular disease (Garcia et al, 1974). Several studies have observed relationships between cardiovascular risk factors and concentrations of proinsulin-like molecules (Nagi et al, 1990; Haffner et al, 1993). Concentrations of proinsulin-like molecules were significantly correlated with total and HDL cholesterol and triglyceride levels, diastolic blood pressure and an inhibitor of fibrinolysis, plasminogen activator inhibitor-1. These relationships, while being interesting, do not demonstrate a causal interaction between proinsulins and any of the cardiovascular risk factors. Data from in vitro studies (Nordt et al, 1994), as well as intervention studies (Jain et al, 1993) suggest that the correlations observed between concentrations of proinsulin-like molecules and PAI-1 might represent a cause and effect relationship, although no such evidence exists for relationships with lipids and blood pressure.