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Biomedical subjects

L C Groop

Publications and source records attributed to L C Groop.

89 records · Page 5Linked to original sources
PubMed1990

Combined insulin-sulfonylurea therapy in treatment of NIDDM.

For the past few years, interest has focused on the combination of insulin and sulfonylurea in the search for effective treatments for non-insulin-dependent diabetes mellitus (NIDDM) patients who fail on oral hypoglycemic agents. Although several studies have demonstrated beneficial effects of such therapy in NIDDM patients, the average effect is small and is observed in only about half of the patients. However, there are several problems with most previous studies, including small sample size, selection of patients, and simultaneous use of several end points. First, residual beta-cell function has been considered to be a prerequisite for a beneficial effect of combination therapy. Therefore, most studies have failed to demonstrate improved glycemic control after adding sulfonylurea to insulin therapy in patients with insulin-dependent diabetes mellitus. Inclusion of patients with impaired beta-cell function will therefore attenuate the effect of combination therapy. Second, most studies have used glycemic control as an end point. Nevertheless, the insulin dose has been reduced by 20-30% to avoid hypoglycemia after adding sulfonylurea to insulin. Thus, the comparison has been made between treatments with a smaller insulin dose with sulfonylurea and a larger insulin dose without sulfonylurea. The patient most likely to benefit from combination therapy is slightly obese, has had NIDDM for a relatively short period, and has preserved beta-cell function. In such a patient, combined insulin-sulfonylurea therapy predominantly stimulates basal insulin secretion, resulting in more effective suppression of hepatic glucose production and lower fasting plasma glucose. The side effects are few, most notably more frequent but mild hypoglycemic reactions.

Diabetes Mellitus, Type 2↗
PubMed1989

Hyperglycaemia and absorption of sulphonylurea drugs.

To examine whether hyperglycaemia impairs the absorption of sulphonylurea agents, glipizide, which is rapidly and completely absorbed, was measured in plasma from 12 healthy young subjects during various levels of experimentally-induced hyperglycaemia. An increase in the plasma glucose concentration above 7 mmol/l was associated with a dose-dependent delay in the absorption of glipizide; at a concentration above 11 mmol/l, the plasma glipizide concentration was reduced by 50%. The data indicate that hyperglycaemia may delay the absorption of sulphonylurea agents, probably because it impairs gastric motility and/or gastric emptying. This delay of absorption may be clinically relevant, since the efficacy of short-acting sulphonylureas is dependent upon the absorption rate of the drug.

Adult↗
PubMed1989

Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance.

The effect of graded, physiologic hyperinsulinemia (+5, +15, +30, +70, +200 microU/ml) on oxidative and nonoxidative pathways of glucose and FFA metabolism was examined in nine lean non-insulin dependent diabetic patients (NIDDM) and in eight age- and weight-matched control subjects. Glucose and FFA metabolism were assessed using stepwise insulin clamp in combination with indirect calorimetry and infusion of [3H]3-glucose/[14C]palmitate. The basal rate of hepatic glucose production (HGP) was higher in NIDDM than in control subjects, and suppression of HGP by insulin was impaired at all but the highest insulin concentration. Glucose disposal was reduced in the NIDD patients at the three highest plasma insulin concentrations, and this was accounted for by defects in both glucose oxidation and nonoxidative glucose metabolism. In NIDDs, suppression of plasma FFA by insulin was impaired at all five insulin steps. This was associated with impaired suppression by insulin of plasma FFA turnover, FFA oxidation (measured by [14C]palmitate) and nonoxidative FFA disposal (an estimate of reesterification of FFA). FFA oxidation and net lipid oxidation (measured by indirect calorimetry) correlated positively with the rate of HGP in the basal state and during the insulin clamp. In conclusion, our findings demonstrate that insulin resistance is a general characteristic of glucose and FFA metabolism in NIDDM, and involves both oxidative and nonoxidative pathways. The data also demonstrate that FFA/lipid and glucose metabolism are interrelated in NIDDM, and suggest that an increased rate of FFA/lipid oxidation may contribute to the impaired suppression of HGP and diminished stimulation of glucose oxidation by insulin in these patients.

Blood Glucose↗
PubMed1988

Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis.

The effect of low-dose insulin treatment (5-10 U/h) on hepatic glucose production (HGP) and peripheral glucose disposal was determined in 5 insulin-dependent diabetes mellitus (IDDM) subjects who were admitted with diabetic ketoacidosis (DKA; plasma glucose 598 +/- 50 mg/dl, blood pH 7.20 +/- 0.06, plasma bicarbonate 12 +/- 2 meq/L). Basal hepatic glucose production (4.3 +/- 0.5 mg.kg-1.min-1) in the DKA patients was 1.5- to 2-fold greater (P less than .01) than in controls (2.1 +/- 0.1 mg.kg-1.min-1) and nonketotic IDDM subjects (2.9 +/- 0.3 mg.kg-1.min-1), whereas tissue glucose disposal was significantly reduced (1.7 +/- 0.1 vs. 2.1 +/- 0.1 mg.kg-1.min-1, P less than .05). After the institution of insulin therapy (1 mU.kg-1.min-1), the plasma glucose concentration fell at the rate of 60 +/- 5 mg.dl-1.h-1 to reach a value of 220 +/- 10 mg/dl, which was maintained constant for 2 h (insulin-clamp technique). Blood pH (7.21 +/- 0.06 to 7.35 +/- 0.05) and plasma bicarbonate (12 +/- 3 to 18 +/- 2 meq/L) both increased during insulin therapy (P less than .01). The decline in plasma glucose concentration during insulin therapy primarily resulted from a suppression of HGP (from 4.3 +/- 0.5 to 1.7 +/- 0.2 mg.kg-1.min-1, P less than .01) and to a lesser extent from the stimulation of tissue glucose disposal (1.7 +/- 0.2 to 2.6 +/- 0.3 mg.kg-1.min-1, P less than .01). At this time, urine glucose excretion decreased from 2.6 +/- 0.2 to 0.6 +/- 0.1 mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1987

The effect of dexamethasone on the enteroinsular axis.

In order to examine whether hyperinsulinaemia induced glucocorticoid therapy involves alterations of the enteroinsular axis glucose, insulin, C-peptide, glucagon and GIP responses to a test meal with and without prior intake of dexamethasone (2 + 2 mg) in 13 healthy subjects were measured. Dexamethasone caused impaired glucose tolerance, which was associated with an exaggerated insulin (0.61 +/- 0.05 vs. 0.38 +/- 0.05 nmol/l; p less than 0.001). C-peptide (0.97 +/- 0.08 vs. 0.71 +/- 0.06 nmol/l; p less than 0.001) and glucagon response to a test meal. In contrast, the GIP response to the test meal was blunted after dexamethasone (126 +/- 17 vs. 177 +/- 23 pmol/l; p less than 0.001). It therefore follows that alterations in the enteroinsular axis, that is, GIP secretion, cannot be responsible for the enhancement of insulin secretion observed after dexamethasone. The mechanism(s) for the decreased GIP response after dexamethasone could involve (1) a direct inhibitory effect on GIP secretion by dexamethasone, and/or (2) a negative feedback of elevated glucose and insulin levels on GIP secretion.

Adult↗
PubMed1986

Risk factors and markers associated with proliferative retinopathy in patients with insulin-dependent diabetes.

To define risk factors and markers associated with proliferative retinopathy (PR), we compared 44 insulin-dependent diabetic patients with PR with 45 matched patients without advanced retinopathy (NR). Glycemic control assessed by HbA1 measurements from 5 yr preceding diagnosis of PR was significantly worse than in NR patients. The NR patients had more frequently been treated with multiple daily insulin injections than the PR patients. About half of the PR patients had Albustix-positive proteinuria, and these patients were further characterized by an abnormal lipid profile in plasma and increased frequency of cardiovascular disease. In contrast, PR patients without proteinuria did not differ from NR patients in these variables. Sensorimotor and autonomic neuropathy were twice as frequent in the PR than in the NR group. There was no correlation between anti-insulin antibody titer, immune complexes, and the presence of PR, but T-lymphocyte response to different stimuli was slightly reduced in the PR patients. The anti-insulin-antibody titer correlated with duration of diabetes in the NR but not the PR group. The frequency of HLA-DRw8 was slightly higher in the PR group than in the NR group (16 vs. 0%, NS), but we could not confirm the previously suggested association between HLA-DR4 and PR. Serum C4 levels were low in the diabetics but did not differ between PR patients without proteinuria and NR patients. In conclusion, poor glycemic control was clearly associated with PR in this study, and attempts to prevent this hazardous complication should include means to improve insulin therapy. We did not find support for the view that susceptibility to PR is associated with any known HLA antigen(s).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis.

One hundred fifty-four selected patients with nonketotic diabetes diagnosed between the ages of 35 and 75 yr and treated with diet or oral hypoglycemic agents for at least 1 yr were investigated for parameters of glycemic control (weight loss, blood glucose, and glycosylated hemoglobin), islet cell function (fasting and glucagon-stimulated C-peptide responses), and immunologic markers of insulitis (total ICA and CF-ICA) or autoimmunity (thyroid and gastric antibodies). These parameters were all repeated in 9 of 22 ICA-positive patients after a 2-yr follow-up and correlated with secondary drug failure. The antibody tests were also done on 51 nondiabetic controls matched for age and body weight. The 22 (14%) diabetic subjects having positive islet cell antibodies (ICA) included more women than men with a shorter duration of symptoms, lower body weight, more associated thyroid autoimmunity, and a tendency to have more type I diabetes in their families, although glycemic control, age at onset, and family history of type II diabetes were the same as in the 132 ICA-negative cases. Patients with ICA had lower initial C-peptide levels and showed little rise after glucagon stimulation. Beta cell function deteriorated significantly during the 2-yr follow-up in 9 of 22 positive patients and more ICA-positive patients required insulin. It is suggested that these latent type I diabetic patients are characterized by persistent ICA, progressive loss of beta cells, and a high frequency of thyrogastric autoimmunity. The determination of ICA may be of clinical value in the diagnosis and treatment of nonketotic diabetes with onset in later life.

Adult↗
PubMed1985

Effect of serial test meals on plasma immunoreactive GIP in non-insulin dependent diabetic patients and non-diabetic controls.

Previous reports have shown considerable variation in postprandial gastric inhibitory polypeptide (GIP) response in non-insulin-dependent diabetic (NIDD) patients. One reason for this may be the use of different GIP antisera. Employing antiserum R65, which specifically reacts with the 5000-dalton GIP, we investigated the plasma GIP response to serial test meals in 11 NIDD patients and 11 age- and weight-matched non-diabetic controls. The postprandial GIP response was lower in the NIDD patients than in the non-diabetic controls (p less than 0.05). Although the serum insulin concentrations did not differ between diabetic and non-diabetic subjects, the insulin to glucose ratio was lower in the diabetics than in the non-diabetic subjects (p less than 0.05) indicating some degree of relative insulin deficiency in the diabetic patients. The data suggest that the GIP secretory capacity may be impaired in NIDD patients. Whether the impairment of GIP secretion is associated with impaired insulin secretion requires further investigation.

Adult↗
PubMed1982

No effect of propranolol and metoprolol on tolbutamide-stimulated insulin-secretion in hypertensive diabetic and non-diabetic patients.

In a double-blind cross-over study, we compared the effects of placebo, propranolol and metoprolol on tolbutamide-stimulated insulin-secretion in 10 non-insulin-dependent hypertensive diabetics and in 10 hypertensive non-diabetic patients. The patients were randomly allocated to two weeks each of treatment with placebo, propranolol 80 mg or metoprolol 100 mg b.i.d. At the end of each period, an intravenous tolbutamide tolerance test (IVTT, 200mg of tolbutamide i.v.) was performed, which caused a significant rise in peripheral insulin levels, leaving blood glucose concentrations unchanged. Tolbutamide-induced insulin-secretion was unaffected by pretreatment with beta-blockers when blood glucose concentrations were unchanged during the test. Since the serum-concentrations achieved with 200 mg of tolbutamide i.v. are similar to those reported during oral tolbutamide therapy, there seems to be no clinically significant interaction between beta-blockers and tolbutamide with respect to insulin-secretion.

Clinical Trials as Topic↗
PubMedDate not supplied

The acute effect of preprandial exogenous and endogenous sulphonylurea-stimulated insulin secretion on postprandial glucose excursions in patients with type 2 diabetes.

Sulphonylureas improve glucose tolerance by stimulating insulin secretion. Whether improved glucose tolerance results from enhanced early insulin release or greater total insulin secretion is not clear. Insulin response to a test meal in Type 2 diabetic subjects with and without a single dose (2.5 mg) of oral and intravenous glipizide were, therefore, measured. Intravenous glipizide enhanced early insulin release more than oral glipizide (134% and 80% vs control; p < 0.01), whereas total insulin release was equally improved (78% and 54% vs control; p < 0.01). Despite slight differences in insulin release, there was no difference in glucose tolerance (median area under concentration curve (AUC); 66.6 vs 61.9 mmol x min l-1; NS). The test meal was repeated after a bolus of intravenous insulin at the beginning of the meal. This allowed comparison of the effect of exogenous and endogenous insulin supply on postprandial glucose excursions. In spite of an early and fivefold larger rise in serum insulin after intravenous administration of the hormone than after intravenous glipizide (725% vs 134%; p < 0.01), postprandial glucose was no better than after glipizide (median AUC; 87.8 vs 66.6 mmol x min l-1; NS). In contrast, glucose tolerance was better after oral glipizide compared to intravenous insulin (median AUC; 61.9 vs 87.8 mmol x min l-1; p < 0.05). In conclusion, the total amount of insulin secreted seems more important than the timing of the insulin release for the postprandial glucose tolerance in Type 2 diabetic subjects. Neither endogenous nor peripheral premeal supply of insulin could normalize postprandial glucose excursions in patients with Type 2 diabetes.

Administration, Oral↗
PubMedDate not supplied

Estimation of blood flow heterogeneity in human skeletal muscle using intravascular tracer data: importance for modeling transcapillary exchange.

Distributed models of blood-tissue exchange are widely used to measure kinetic events of various solutes from multiple tracer dilution experiments. Their use requires, however, a careful description of blood flow heterogeneity along the capillary bed. Since they have mostly been applied in animal studies, direct measurement of the heterogeneity distribution was possible, e.g., with the invasive microsphere method. Here we apply distributed modeling to a dual tracer experiment in humans, performed using an intravascular (indocyanine green dye, subject to distribution along the vascular tree and confined to the capillary bed) and an extracellular ([3H]-D-mannitol, tracing passive transcapillary transfer across the capillary membrane in the interstitial fluid) tracer. The goal is to measure relevant parameters of transcapillary exchange in human skeletal muscle. We show that assuming an accurate description of blood flow heterogeneity is crucial for modeling, and in particular that assuming for skeletal muscle the well-studied cardiac muscle blood flow heterogeneity is inappropriate. The same reason prevents the use of the common method of estimating the input function of the distributed model via deconvolution, which assumes a known blood flow heterogeneity, either defined from literature or measured, when possible. We present a novel approach for the estimation of blood flow heterogeneity in each individual from the intravascular tracer data. When this newly estimated blood flow heterogeneity is used, a more satisfactory model fit is obtained and it is possible to reliably measure parameters of capillary membrane permeability-surface product and interstitial fluid volume describing transcapillary transfer in vivo.

Blood Flow Velocity↗
PubMedDate not supplied

Secondary failure to treatment with oral antidiabetic agents in non-insulin-dependent diabetes.

To study the etiopathogenesis of secondary drug failure to treatment with oral antidiabetic agents in patients with non-insulin-dependent diabetes (NIDD) we compared 60 "nonresponders" with 60 "responders" to treatment with oral drugs. Secondary drug failure was defined as mean diurnal blood glucose greater than 12 mmol/L after an initial good response of greater than or equal to 2 yr. The nonresponders were characterized by 50% lower C-peptide concentrations than the responders (P less than 0.001). We could not, however, define a critical C-peptide level to discriminate between patients requiring and not requiring insulin therapy. There was a wide overlap of individual C-peptide values between responders and nonresponders that attenuates the clinical value of single C-peptide measurements in predicting therapy. Only by serial measurements over a period of time was it possible to achieve information about changes in beta cell function. The nonresponders showed increased frequency of islet cell (P less than 0.01), thyroid antimicrosomal (P less than 0.01), and gastric parietal cell antibodies (P less than 0.02). In nonresponders, HLA-antigen B8 was increased (P less than 0.05) and HLA-B7 decreased (P less than 0.01) compared with frequencies of responders. In conclusion, impaired beta cell function is a characteristic feature of many, but not all, NIDD patients who fail on treatment with oral antidiabetic drugs. The presence of islet cell and thyrogastric antibodies can unmask a distinct group of NIDD patients with a high risk of secondary drug failure and subsequent insulin dependency. HLA typing may further help to predict secondary failure in NIDD.

Administration, Oral↗