Beta-cell Function In Type Research Articles

Elevated plasma non-esterified fatty acid levels and insulin secretion in non-diabetic relatives of type 2 diabetic patients.

High non-esterified fatty acid (NEFA) levels impair glucose-stimulated insulin secretion from islets derived from non-diabetic Zucker rats that are genetically predisposed to diabetes. We therefore examined the effect of elevated plasma NEFA levels on insulin secretion in non-diabetic first-degree relatives of type 2 diabetic patients who are at increased risk of developing diabetes. Normal glucose tolerant relatives (n = 9) and control subjects with no family history of diabetes were pair-matched for age, sex, body mass index (BMI), insulin sensitivity and early insulin response during an oral glucose tolerance test (OGTT). Plasma NEFA levels were raised from 0 to 340 minutes by the infusion of 20% Intralipid and heparin. From 180 minutes, insulin secretion rates (IRSs) were assessed by stepped low-dose glucose infusion. The mean (geometric mean +/- 95% CI) NEFA levels were comparable between relatives and control subjects (2.7 [2.1-3.6] and 2.1 [1.7-2.7] mmol/l, paired analysis, NS). Similarly, plasma glucose levels achieved at each glucose infusion step were comparable between the groups. However, there were no significant differences between the groups for ISR throughout the study. Sustained elevation of plasma non-esterified fatty acid levels does not decrease insulin secretion in non-diabetic relatives of type 2 diabetic patients, and is therefore unlikely to be important in the development of the impaired pancreatic beta-cell function in type 2 diabetes mellitus.

Addressing the insulin secretion defect: A logical first-line approach

The pathogenesis of type 2 diabetes has been an area of intense investigation, considerable controversy, and continuing discovery. It is now clear that this is a heterogeneous condition both phenotypically and genotypically, and that acquired reversible abnormalities/risk factors also play an important role. Currently, type 2 diabetes can be viewed as developing in genetically susceptible individuals, who, because of impaired beta-cell function, are incapable of increasing their insulin release appropriately to compensate for reduced insulin sensitivity which is acquired through life for various reasons (eg, obesity, aging, physical inactivity, drug use, or diet). As our knowledge of the interplay of these elements increases, there will be important consequences regarding the choice of the most appropriate therapeutic approach for individual patients. This review will analyze issues pertaining to the interaction of reduced insulin sensitivity and impaired beta-cell function in type 2 diabetes, specifically: which is the primary genetic factor, which is more important in determining hyperglycemia, what is the most important site affected by impaired beta-cell function and insulin sensitivity, and which, if any, should be the preferential target for therapeutic intervention.

Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal streptozotocin-treated rats.

According to the "glucose toxicity" hypothesis, hyperglycemia contributes to defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus. This concept is supported by substantial data in rodent models of diabetes. However, the ability of glucose to stimulate the accumulation of insulin mRNA, a critical feature of normal beta-cell physiology, has not been investigated in in vivo models with chronic hyperglycemia. The aim of this study was to determine whether glucose-induced insulin mRNA accumulation is impaired in the neonatal streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin-dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/l glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA levels were increased more than twofold by glucose in control islets. In contrast, no significant effect of glucose was found on insulin mRNA levels in n0-STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0-STZ rat islets.

Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus

On the basis of a retrospective study of 71 children followed for 24 months after diagnosis of type I insulin dependent diabetes a fitted mathematical model was constructed for the prediction of the course of beta cell function from the time of diagnosis. Two equations were derived, one for the maximal basal (B-max) and the other for the maximal i.v. glucagon stimulated peak C-peptide (P-max) levels reached during the remission period. The prognostic variables selected for analysis were: peak C-peptide levels at diagnosis (Po), age, sex, degree of obesity, pubertal rating, the presence of islet cell antibodies (ICA) and levels of GHb. Multivariate analysis of the data showed that Po (p = 0.0006), puberty (p = 0.041), obesity (p = 0.0021), sex (p = 0.031), ICA (p = 0.0045) and GHb (p = 0.0066) significantly contributed to the prediction formula obtained for B-max whereas the contribution of the above variables for P-max were: Po (p = 0.0019), puberty (p = 0.0187), obesity (p = 0.0058), sex (p = 0.0598), ICA (p = 0.0187) and GHb (p = 0.0027). The residuals of the observed values from the values fitted by the predicted equations served to define two separate groups demonstrating distinct differences in the natural course of beta cell function in type I diabetes. This fitted model may thus be useful in distinguishing between newly diagnosed young patients who will undergo remission, requiring lower insulin doses, and those who have little chance for remission. It might also be helpful in the selection of patients most likely to benefit from immunosuppression or modulation, to maximize the benefit to risk ratio for such patients.

In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

We investigated the importance of the level and the duration of glucose stimulation on the in vivo and in vitro insulin response to glucose in normal rats previously submitted to hyperglycaemia. Rats were made hyperglycaemic by a 48-h glucose infusion. Glucose-induced insulin secretion was investigated in vivo by a 20-min hyperglycaemic clamp and in vitro by the isolated perfused pancreas technique, 3 h after the end of the in vivo glucose infusion. In glucose-infused rats, as compared to controls, in vivo incremental plasma insulin values above baseline integrated over the 20-min hyperglycaemic clamp (delta I) were five times higher during 8 mmol/l glucose clamp, only two times higher in 11 mmol/l glucose clamp and no different in 16.5 mmol/l. Compared to the controls, in vitro incremental plasma insulin concentration above baseline integrated over a 20-min period (delta I) in glucose-infused rats was 16 times higher in response to 2.8 mmol/l glucose, two times higher in response to 5.5 mmol/l, similar in response to 8.3 mmol/l and significantly lower in response to 16.5 mmol/l. In conclusion, our data suggest that a 48-h hyperglycaemic period results in an increased response of the pancreatic beta cell to low glucose. The response is immediately maximal and can not be increased with higher glucose concentrations. This situation could explain the apparent minimal effect of high concentrations on in vitro insulin secretion in previously hyperglycaemic rats and may provide insights into the sequence of events leading to the impairment of beta-cell function in Type 2 (non-insulin-dependent) diabetes mellitus.

Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse

Early intensive insulin treatment is thought to improve subsequent Beta-cell function in Type 1 (insulin-dependent) diabetic patients. Prophylactic insulin administration also reduced diabetes incidence in diabetes-prone animals. To study the mechanisms by which these effects occur, we tested the ability of insulin therapy in the model of non-obese-diabetic mice, to prevent the penetration of committed T cells into the islets and subsequent Beta-cell destruction. Sublethally irradiated non-obese-diabetic males of 8 weeks of age were adoptively transferred with splenocytes from diabetic donors and treated with the maximum tolerable dosage of fast-acting insulin (0.5 U, twice daily) until 30 days after cell transfer. Diabetes incidence was compared to control animals injected with the same concentration of insulin diluent. After one month of treatment, the cumulative diabetes frequency was significantly less within the insulin-treated group (4 of 15, 26.6%) than in the control group (15 of 18, 83.3%; p less than 0.01). Pancreatic histological analysis of insulin-treated animals revealed a lower severity of insulitis and Beta-cell necrosis and a higher percentage of normal islets (46.6 +/- 10% vs 2.3 +/- 2%, p less than 0.01), including five (33%) mice with no lesions. Immunoperoxydase staining of pancreatic sections indicated similar insulin and ganglioside staining of Beta cells from insulin-treated mice and control animals. Insulin-treated mice had comparable pancreatic insulin content to normal mice. Flow cytometry analysis of spleen cell populations indicated that insulin increased the number of Thy1,2+ and Lyt-2+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive gastric inhibitory polypeptide response to a meal during the first eighteen months after diagnosis of type 1 (insulin dependent) diabetes mellitus.

The changes in plasma concentrations of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to a standard meal were examined in 21 normal subjects and 15 Type 1 (insulin dependent) diabetic patients 7 days, 14 days, and 3, 6, 9, 12, and 18 months after time of diagnosis. During the first 4 tests significantly lower plasma IR-GIP concentrations were found in the diabetic patients after the standard meal. At 9 months and during the remaining tests there was no difference in IR-GIP concentrations between the diabetic and the normal subjects. The IR-GIP response was normalized faster if the diabetic patients were treated with initial short term intensive insulin therapy than if they were treated conventionally with 1 or 2 daily injections of insulin. beta-Cell function, evaluated by the C-peptide response to the meal, increased significantly during the first 3 months. After 3 months maximal beta-cell function was found while the corresponding IR-GIP responses were significantly lower than those of the normal subjects. Thereafter beta-cell function declined gradually and significantly, coinciding with the normalization of the IR-GIP response. No individual covariation between IR-GIP and beta-cell function during the 18 months was found in any patient. The IR-GIP response to a meal was diminished at the onset of Type 1 (insulin dependent) diabetes mellitus. After the start of insulin therapy the response improved, perhaps as a function of the quality of metabolic control, and within a year it was comparable to that of normal subjects. Lack of endogenous GIP therefore does not explain the diminished beta-cell function in Type 1 diabetes a few months after onset of the disease. No causal relationship between the changes in beta-cell function and IR-GIP during the first 18 months after the onset of the disease seems to exist.

Residual beta-cell function in type II diabetes and evaluation of the hepatic insulin extraction.

Insulin and C-peptide (free insulin and C-peptide in insulin-treated patients) were measured after glucose stimulation in nine Type II diabetics on chlorpropamide, eleven insulin-treated maturity-onset diabetics and in 8 normal controls. Dissociation between C-peptide and insulin response to glucose was observed in several diabetics. The relation between incremental molar areas under C-peptide and insulin curves, after glucose challenge (delta CPR - delta IRI/delta CPR) were used to evaluate the hepatic insulin extraction in all but the insulin-treated diabetics. The lower insulin requirements and better control of the short-duration insulin-treated maturity-onset diabetics in relation to the long-term ones could not be explained either by the residual insulin secretion or by the level of "insulin antibodies". The chlorpropamide-responsive patients presented higher insulin levels after the glucose challenge and a lower hepatic insulin extraction than the non-responsive ones.

Factors of importance for residual beta-cell function in type I diabetes mellitus. A review.

ABSTRACT. With the development of the C‐peptide assay more systematic studies of the endogenous insulin secretion have been possible in insulin‐dependent diabetes. Several reports now support the view that nearly 100% of patients have functioning beta‐cells at onset of disease. After start of insulin therapy most patients have a transient improvement in beta‐cell function, the remission period, with a maximum found between 2 and 5 months after diagnosis. Thereafter the beta‐cell function declines, but after 2 years duration of disease nearly 100% of the patients still will display residual beta‐cell function. The following years the prevalence of residual beta‐cell function will decrease to about 15% after 10 to 15 years duration, and thereafter no further decline in prevalence seems to occur. At present it is unclear why insulin‐dependent patients have different degree of beta‐cell function after years duration of disease. We have demonstrated that age at onset is of importance the first 10–15 years of disease, where the prevalence was highest in the elder patients. Thereafter the age at onset is without influence on prevalence of residual beta‐cell function. The degree of metabolic control is also of importance for beta‐cell function. Both at onset and in patients past their initial remission period has improvement in glucaemic control resulted in an improved beta‐cell function; but disappointingly this effect has only been transient. Whether poor metabolic control accelerates the destruction of the beta‐cells is not known. The importance of the many abnormal immunological parameters found in insulin‐dependent diabetics still has to be elucidated. Until now none of them have shown correlations to residual beta‐cell function. Therefore, at present it is impossible to predict at diagnose and during the first year of disease, which patients who will display residual beta‐cell function throughout life.