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Biomedical subjects

L Groop

Publications and source records attributed to L Groop.

At least 145 records · Page 8Linked to original sources
PubMed1989

Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus.

To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.

Adult↗
PubMed1989

Different effects of insulin and oral antidiabetic agents on glucose and energy metabolism in type 2 (non-insulin-dependent) diabetes mellitus.

Which therapy should be used in Type 2 (non-insulin-dependent) diabetic patients with "secondary sulfonylurea failure", insulin or a combination of sulfonylurea and metformin? To address this question, we have compared the effect of 6 months of insulin therapy twice daily with that of a combination of glibenclamide and metformin in 24 Type 2 diabetic subjects, who no longer responded to treatment with sulfonylureas. Both treatments resulted in an equivalent 30% improvement in mean daily blood glucose (p less than 0.001), without significant effect on serum lipids. Insulin improved glycaemic control primarily by reducing basal hepatic glucose production (p less than 0.05), but had no significant effect on peripheral glucose metabolism. The combination of glibenclamide and metformin enhanced significantly total body glucose metabolism (p less than 0.05), predominantly by stimulating the non-oxidative pathway. Neither insulin nor the combination therapy altered B-cell response to a test meal. Insulin therapy resulted in a 6% increase in body weight, 63% of which was accounted for by increased fat mass. Although body weight was unchanged during sulfonylurea/metformin therapy, lean body mass and energy expenditure decreased significantly (p less than 0.05). We conclude that insulin and glibenclamide/metformin have different long-term effects on glucose and energy metabolism in Type 2 diabetes.

Blood Glucose↗
PubMed1989

Characteristics of non-insulin-dependent diabetic patients with secondary failure to oral antidiabetic therapy.

PURPOSE: Secondary failure to treatment with oral antidiabetic agents frequently occurs in patients with non-insulin-dependent diabetes mellitus. In the search for causes of such failures, we examined patient- and disease-related factors in nonresponders and in responders to treatment with oral antidiabetic agents. PATIENTS AND METHODS: The study population consisted of three groups: (1) 34 nonresponders to treatment with sulfonylureas; (2) 25 patients who still responded to treatment with sulfonylureas; and (3) 10 age-matched healthy control subjects. In addition to patient-related factors such as adherence to diet and knowledge of diabetes, we examined insulin response to a test meal and hepatic and peripheral insulin sensitivity during a euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3-]glucose. RESULTS: Patient-related factors such as daily nutrient intake, activity score, knowledge of diabetes, and "stress level" were similar in both groups. However, nonresponders had a higher rate of basal hepatic glucose production (4.60 +/- 0.14 versus 3.63 +/- 0.26 mg/minute/kg of lean body weight; p less than 0.001), which was less suppressed by euglycemic hyperinsulinemia (about 100 microU/mL) than was that of the responders (p less than 0.001). In addition, total insulin-stimulated glucose metabolism was reduced (5.07 +/- 0.22 versus 7.09 +/- 0.56 mg/kg.LBM.minute; p less than 0.001), and this was mainly accounted for by a reduction in non-oxidative glucose metabolism (glycogen synthesis and anaerobic glycolysis) (1.78 +/- 0.22 versus 3.54 +/- 0.49 mg/kg.LBM.minute; p less than 0.001). The severity of hepatic and peripheral insulin resistance correlated with the plasma glucose concentration but was unrelated to insulin secretion. In a multiple linear regression analysis, glucose overproduction in the liver (26.1%), impaired peripheral glucose metabolism (17.3%), and insulin deficiency (12.6%) could explain only 56% of the causes of secondary drug failure. CONCLUSION: Secondary failure to treatment with oral hypoglycemic agents is determined by the disease itself rather than by patient-related factors. Treatment of secondary drug failure should therefore aim at ameliorating both hepatic and peripheral insulin resistance.

Blood Glucose↗
PubMed1989

Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use.

Apart from the amelioration of symptoms, a major aim of the treatment of non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) should be the prevention of cardiovascular complications. These are associated with the chronic hyperglycaemia that is characteristic of NIDDM, and the risk of complications is already increased in subjects with impaired glucose tolerance (IGT). For these reasons, and because hyperglycaemia appears to be a self-perpetuating condition, treatment should be introduced as early as possible and should be aimed at normalisation of blood glucose. To enable early detection and intervention, screening is necessary. As diet regulation alone rarely suffices to normalise blood glucose, addition of sulphonylurea drugs is indicated in many cases. If introduced in the IGT phase, sulphonylureas drugs combined with diet regulation may postpone the development of IGT to manifest NIDDM, and may reduce the increased risk of cardiovascular morbidity and mortality. Sulphonylureas stimulate insulin release, possibly via interaction with receptors in the pancreatic B cells. In addition, such treatment enhances the reduced insulin action. This might be a primary effect but is also a consequence of the increased access to insulin and the subsequent reduction of hyperglycaemia. Sulphonylureas may enhance insulin availability by reducing insulin clearance. Effects on blood lipids are probably secondary phenomena. Fast and short acting sulphonylureas may improve the impaired meal-induced acute insulin release. If combined with weight-reducing diet regulation and introduced early, such treatment can maintain (near) normal blood glucose levels and an improved insulin action for several years without increasing basal insulin secretion, without chronic hyperinsulinaemia, and without weight increase. If not combined with diet regulation, sulphonylurea therapy is likely to fail. If introduced when NIDDM is advanced, the efficacy of these drugs is limited, with secondary failures developing at a rate of 5 to 10% per year. Continuous (24-hour-a-day) exposure to drug treatment could possibly desensitise the B cell to sulphonylurea stimulation. 'Second-generation' sulphonylurea drugs have a higher potency than 'first-generation' drugs, but this need not signify a greater clinical efficacy. The effect of several of these drugs may be increased if they are ingested half an hour before meal(s). Short acting sulphonylureas may be safer than long acting ones, which seem more likely to cause long lasting and fatal hypoglycaemia, at least in elderly patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1989

Renal papillary necrosis in patients with IDDM.

Although diabetes mellitus is reported in 29% of patients with renal papillary necrosis (RPN), the frequency of RPN among patients with insulin-dependent diabetes mellitus (IDDM) has from autopsy studies been estimated to be only 4.4%. In vivo data on the prevalence of RPN in patients with IDDM have been lacking. We therefore studied the prevalence of RPN in 76 patients with long-standing IDDM and in 34 age-matched control subjects by intravenous urography. None of the control subjects showed radiographic signs of papillary necrosis. RPN was observed in 18 patients (23.7%); 15 were women (83.3%). Age and duration of diabetes was not different between patients with and without papillary necrosis, and there was no significant difference between the two groups regarding the prevalence of microangiopathic complications, i.e., proliferative retinopathy and diabetic nephropathy. Microscopic hematuria was three times more frequent in patients with than without RPN (44 vs. 16%; P less than .02). In addition, pyuria was reported in 40% of patients with papillary necrosis, and 61% of them gave a positive history of urinary tract infection compared to 16% (P less than 05) and 32% (P less than .02), respectively, in patients without papillary necrosis. It is concluded that RPN is a more frequent complication of long-standing IDDM than appreciated from autopsy studies, and being female and having a history of urinary tract infection are associated with an increased risk of RPN.

Adult↗
PubMed1989

Immune responses to insulin in patients with insulin-dependent diabetes mellitus.

To examine the effect of the major histocompatibility locus (HLA) and the duration of insulin-dependent diabetes (IDDM) on immune responses to insulin we assayed insulin induced proliferation of blood mononuclear cells and measured insulin antibodies in 66 patients with newly diagnosed and in 56 patients with longstanding IDDM matched for the age at onset (less than or equal to 15 years). In up to two thirds of the patients blood mononuclear cells responded to insulins by proliferation, and insulin antibodies were found in two thirds of patients with IDDM of long duration. Insulin proliferation or antibodies were not associated to any particular HLA antigen. The frequency of HLA-DR3 in patients with newly diagnosed IDDM was not increased unlike in patients with IDDM of long duration. In addition, HLA-B8 was associated to HLA-DR3 nearly twice as often in patients with newly diagnosed IDDM as in patients with longstanding IDDM. Thus, patients with IDDM of recent onset and diagnosed within the last three years more frequently responded to insulin by proliferation and less often had HLA-DR3 than patients with IDDM of long duration and diagnosed about 20-25 years earlier.

Adult↗
PubMed1989

Mechanisms of insulin resistance after kidney transplantation.

In order to study the effect of corticosteroids on energy metabolism in immunosuppressed patients after kidney transplantation, we have examined glucose utilization, energy expenditure, and lean body mass in 10 kidney-transplanted patients receiving steroids (methylprednisolone 8.2 +/- 1.5 mg/day) and in 10 healthy age- and weight-matched control subjects. Glucose utilization was measured during euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3]-glucose, while beta-cell function was measured during a hyperglycemic clamp. The kidney-transplanted patients were resistant to the glucoregulatory effect of insulin, as demonstrated by a 25% reduction in total glucose disposal compared to control subjects. This defect was almost completely accounted for by a defect in storage of glucose as glycogen (3.3 +/- 0.5 vs. 5.0 +/- 0.5 mg/kg LBM min; P less than 0.05). The reduction in nonoxidative glucose disposal was associated with reduced lean body mass and incapacity to release energy as heat after infusion of insulin, i.e. thermogenic defect. In contrast, oxidation of glucose and lipids was not influenced by steroid therapy. Furthermore, suppression of hepatic glucose production was normal, and insulin secretion was normally enhanced in relation to the degree of insulin resistance in the steroid-treated patients. In conclusion, steroid-induced insulin resistance in kidney-transplanted patients is due to alterations in the nonoxidative pathway of glucose metabolism. These findings raise the question of whether steroid therapy directly influences glycogen synthase in man.

Adrenal Cortex Hormones↗
PubMed1988

Effects of the combination of insulin and glibenclamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents.

The effects of combined insulin and sulfonylurea therapy on glycaemic control and B-cell function was studied in 15 Type 2 (non-insulin-dependent) diabetic patients who had failed on treatment with oral hypoglycaemic agents. The patients were first treated with insulin alone for four months. Five patients were given two daily insulin doses and ten patients one dose. During insulin treatment the fasting plasma glucose fell from 14.5 +/- 0.8 to 8.8 +/- 0.4 mmol/l and the HbA1 concentration from 12.6 +/- 0.4 to 9.2 +/- 0.2%. This improvement of glycaemic control was associated with a suppression of basal (from 0.31 +/- 0.04 to 0.10 +/- 0.02 nmol/l) and glucagon-stimulated (from 0.50 +/- 0.08 to 0.19 +/- 0.04 nmol/l) C-peptide concentrations. Four months after starting insulin therapy the patients were randomised to a four-month double-blind cross-over treatment with insulin combined with either 15 mg glibenclamide per day or with placebo. Addition of glibenclamide to insulin resulted in a further reduction of the fasting plasma glucose (7.9 +/- 0.5 mmol/l) and HbA1 (8.3 +/- 0.2%) concentration whereas the basal (0.21 +/- 0.03 nmol/l) and glucagon-stimulated C-peptide concentrations (0.34 +/- 0.06 nmol/l) increased again. Addition of placebo to insulin had no effect. The daily insulin dose could be reduced by 25% after addition of glibenclamide to insulin, while it remained unchanged when insulin was combined with placebo. The fasting free insulin concentration did not differ between the glibenclamide and placebo periods (28 +/- 6 vs 30 +/- 5 mmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes.

Islet cell antibodies (ICAs), thyrogastric antibodies, and HLA-DR antigens were determined in 204 patients with type II (non-insulin-dependent) diabetes controlled with diet and/or oral hypoglycemic agents (NIR) and in 108 age-matched patients who required insulin to control their hyperglycemia (IR). beta-Cell function measured as C-peptide response to glucagon was evaluated in relation to the presence of ICAs and HLA-DR antigens. The IR patients differed from the NIR patients with respect to higher frequency of ICAs (P less than .001), thyroid antibodies (P less than .02), and the HLA antigen DR4 (P less than .02). The highest frequency of ICAs and thyroid antibodies was observed in female insulin-treated subjects (51.2 and 46.4%). Patients who were heterozygous for HLA-DR3/DR4 showed significantly higher frequency of ICAs (P less than .01) and complement-fixing ICAs (P less than .001) than patients without the heterozygous form DR3/DR4. Neither the presence of ICA alone nor DR3/DR4 alone was associated with a significant impairment of beta-cell function. However, when both ICA and DR3/DR4 were present in a diabetic individual, beta-cell function was markedly impaired (P less than .001), suggesting that both genetic and autoimmune factors are necessary to facilitate the process leading to beta-cell destruction of the patients. Our findings suggest that type II diabetes is a heterogeneous disorder including at least two major subgroups, which can be further characterized by HLA-DR antigens and organ-specific antibodies.

Autoantibodies↗
PubMed1988

HLA-antigens and immunity to insulin in insulin-dependent diabetics with or without diabetic neuropathy.

In order to define genetic, immunological and metabolic risk factors and markers associated with diabetic neuropathy (DN) 47 insulin-dependent diabetic patients with neuropathy were compared to 30 age-matched insulin-dependent diabetes mellitus (IDDM) patients without neuropathy. Patients with diabetic neuropathy more often had proliferative retinopathy and Albustix positive proteinuria than patients without neuropathy. Judged by haemoglobin A1 (HbA1) concentrations measured during the preceding two years glycaemic control was worse in patients with than without diabetic neuropathy. The frequency of HLA-antigens DR3, DR4, DR3/DR4, B8, and B15 were increased and those of DR2 and B7 decreased in the diabetic patients. The frequency of any of these HLA-antigens did not differ in patients with or without diabetic neuropathy. There were no significant differences in the frequencies of insulin antibodies or proliferative responses to insulin antigens between patients with or without diabetic neuropathy. However, patients who were HLA-DR3/DR4 heterozygotes and had diabetic neuropathy responded to insulin antigens more often by proliferation than DR3/DR4 positive patients without diabetic neuropathy. Thus poor glycaemic control is associated with an increased risk for diabetic neuropathy. Patients with DR3/DR4 heterozygocity and failing to respond to insulin antigens by proliferation seem to be less prone to develop diabetic neuropathy.

Adult↗
PubMed1987

Outcome of patients with diabetic nephropathy after kidney transplantation.

During the period 1973-1983, 1,014 patients with end stage renal failure received a kidney graft at the Helsinki University Central Hospital. As a consequence of diabetic nephropathy, 163 of them (16%) developed renal failure. Ten diabetic (6%) and 72 non-diabetic (9%) patients received grafts from a living donor. One-year patient survival did not differ between diabetic and non-diabetic patients (76% and 79%, respectively). From the second post-transplant year onwards patient survival was worse in diabetic than in non-diabetic patients. The two groups did not differ with respect to graft survival. Sixty-two diabetic patients (38%) died during the follow-up period, with myocardial infarction as the most common cause of death (31%), followed by infection (15%) and cerebral stroke (13%). Seven myocardial infarctions out of 19 occurred within three months of transplantation. However, significantly more fatal and non-fatal myocardial infarctions were observed in post-transplant patients who had returned to dialysis therapy than in patients with a functioning kidney graft. Blindness did not influence the outcome of transplantation. Nor did the transplantation significantly affect the course of this diabetic complication. In conclusion, although the early success rate of kidney transplantation in our study population was acceptable, the later outcome was poor, mainly due to advanced disease-related complications.

Cardiovascular Diseases↗
PubMed1987

Different effects of glyburide and glipizide on insulin secretion and hepatic glucose production in normal and NIDDM subjects.

Glyburide (GB) and glipizide (GZ) differ in their pharmacokinetics, but it is not known whether they also differ in mode of action. To examine this question, 10 young healthy subjects and 6 non-insulin-dependent diabetic (NIDDM) patients participated in each of three studies: 1) infusion of saline for 120 min followed by a 100-min hyperglycemic (125 mg/dl) clamp; 2) 120-min primed continuous infusion of GZ followed by a 100-min hyperglycemic clamp; and 3) 120-min primed continuous infusion of GB followed by a 100-min hyperglycemic clamp. The GB and GZ infusions were continued throughout the hyperglycemic clamp. Similar plasma concentrations of GB and GZ were obtained in both groups. All studies were performed with [3-3H]glucose to allow quantification of hepatic glucose production. When administered under basal conditions of glycemia, the acute phase (0-10 min) of plasma insulin and C-peptide increase in both control and NIDDM subjects was twice as great with GZ compared with GB (P less than .01). During the hyperglycemic-clamp studies performed in normal subjects, both GB and GZ increased the first- (1.6-fold) and second- (2.2-fold) phase plasma insulin responses more than hyperglycemia alone. During the hyperglycemic clamp in NIDDM subjects, the first-phase plasma insulin response was absent, and the second-phase insulin response was markedly impaired. Neither GB nor GZ improved first-phase insulin secretion in the NIDDM patients. In both NIDDM and control subjects, the effects of hyperglycemia and sulfonylurea drugs (both GB and GZ) on the first- and second-phase plasma insulin responses were simply additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients.

Glycemic control and glucose metabolism were examined in 5 patients with insulin-dependent diabetes mellitus (IDDM) and 8 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients before and after 2 mo of therapy with glyburide (20 mg/day). Glycemic control was assessed by daily insulin requirement, 24-h plasma glucose profile, glucosuria, and glycosylated hemoglobin. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, and insulin sensitivity was determined by a two-step euglycemic insulin clamp (1 and 10 mU X kg-1. X min-1) performed with indirect calorimetry and [3-3H]glucose. In the IDDM patients, the addition of glyburide produced no change in daily insulin dose (54 +/- 8 vs. 53 +/- 7 U/day), mean 24-h glucose level (177 +/- 20 vs. 174 +/- 29 mg/dl), glucosuria (20 +/- 6 vs. 35 +/- 12 g/day) or glycosylated hemoglobin (10.1 +/- 1.0 vs. 9.5 +/- 0.7%). Furthermore, there was no improvement in basal hepatic glucose production (2.1 +/- 0.2 vs. 2.4 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by low- and high-dose insulin infusion, or in any measure of total, oxidative, or nonoxidative glucose metabolism in the basal state or during insulin infusion. C-peptide levels were undetectable (less than 0.01 pmol/ml) in the basal state and after glucagon infusion and remained undetectable after glyburide therapy. In contrast to the IDDM patients, the insulin-treated NIDDM subjects exhibited significant reductions in daily insulin requirement (72 +/- 6 vs. 58 +/- 9 U/day), mean 24-h plasma glucose concentration (153 +/- 10 vs. 131 +/- 5 mg/dl), glucosuria (14 +/- 5 vs. 4 +/- 1 g/day), and glycosylated hemoglobin (10.3 +/- 0.7 vs. 8.0 +/- 0.4%) after glyburide treatment (all P less than or equal to .05). However, there was no change in basal hepatic glucose production (1.7 +/- 0.1 vs. 1.7 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by insulin, or insulin sensitivity during the two-step insulin-clamp study. Both basal (0.14 +/- 0.05 vs. 0.32 +/- 0.05 pmol/ml, P less than .05) and glucagon-stimulated (0.24 +/- 0.07 vs. 0.44 +/- 0.09 pmol/ml) C-peptide levels rose after 2 mo of glyburide therapy and both were correlated with the decrease in insulin requirement (basal: r = .65, P = .08; glucagon stimulated: r = .93, P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗