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The Diabetes Control and Complications Trial was conducted in heavily-equipped centres on a selected and motivated patient cohort. The aim of the present study was to evaluate at one-year follow-up the results of intensive insulin therapy in patients with insulin-dependent diabetes mellitus attending a department of diabetology. From October 1, 1993, to December 31, 1994, all our hospitalised patients under 55 years of age with HbA1c levels above 8% and receiving 2 daily insulin injections were offered the opportunity to shift to 3 daily injections (short-acting insulin in the morning and at midday, and a mixture of short-acting and intermediate insulin in the evening). Patients were instructed to increase blood glucose self-monitoring and to see their diabetologist more often (once every two months). Five patients refused and 45 accepted this proposal: 22 women and 23 men (mean age 31.8 +/- 10.9 yr), BMI 23.5 +/- 2.9 kg/m2, duration of diabetes 12.8 +/- 10.1 yr, HbA1c 10.0 +/- 2.0%. Five patients were lost to follow-up, 2 asked to have their medical file transferred, 3 returned to 2 daily injections, and 5 consulted only once during the year of follow-up. For the 29 patients seen after one-year follow-up, the decrease in HbA1c levels from 10.0 +/- 1.9% to 9.5 +/- 1.8% was not statistically significant. Sixteen patients complained of increased occurrence of hypoglycaemia (3 comas). In routine clinical practice, the prescription of intensive insulin therapy to non-selected insulin-dependent diabetic patients can be associated with a high number of patients lost to follow-up (17% in our study). An increase in the number of daily insulin injections will improve glycaemic control only if self-monitoring and medical surveillance are also intensified. However, many long-term poorly-controlled insulin-dependent diabetic patients are reluctant to comply with these recommendations.

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.

The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperinsulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU.kg body weight.min-1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU.kg body weight-1.min-1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.

Objective: In eight glucokinase (GCK)-deficient subjects, we have investigated insulin secretion rates (ISRs) in response to intravenous arginine. Impairment in the enzymatic activity of mutant GCK leads to a reduced glycolytic flux in beta-cells. This defect translates in vivo as a right shift in the glucose/SR dose-response curve. Insulin secretion in response to other secretagogues has not been reported., Research Design and Methods: The arginine test was performed immediately after a 2-h hyperglycemic (10 mM) clamp. ISR was computed by deconvolution of peripheral C-peptide levels. Linear regression analyses were performed to assess correlations between the beta-cell secretory responses to the arginine test, an intravenous glucose tolerance test (IVGTT), and a hyperglycemic clamp (areas under the C-peptide curves), and between these parameters and the glucose tolerance status (area under the glucose curve during an oral glucose tolerance test)., Results: Two minutes after the injection of arginine, the increment in ISR was 30.17 +/- 10.01 pmol insulin.kg-1.min-1 in patients and 36.25 +/- 15.46 pmol insulin.kg-1.min-1 in control subjects (P = 0.38). Throughout the experiment, increments in ISR were comparable in both groups. The amount of insulin secreted in response to arginine (0-5 min) was similar in patients and control subjects: 81 +/- 28 vs. 119 +/- 55 pmol/kg (P = 0.16), respectively. The arginine test C-peptide response was not correlated with the IVGTT or hyperglycemic clamp responses. The arginine test and hyperglycemic clamp responses were not correlated to the glucose tolerance status. The best predictor of the glucose tolerance was the C-peptide response to the IVGTT (r2 = 0.78; P = 0.002)., Conclusions: beta-cell secretory increment in response to arginine was found to be in the normal range in GCK-deficient subjects. The arginine test does not seem to reflect either the beta-cell secretory defect or the glucose tolerance status of these subjects. IVGTT seems to be the best predictor of the latter parameter in this population.

Pancreatic beta-cell function was studied in six subjects with mutations in the enzyme glucokinase (GCK) who were found to have elevated fasting and postprandial glucose levels in comparison to six normoglycemic controls. Insulin secretion rates (ISRs) were estimated by deconvolution of peripheral C-peptide values using a two-compartment model and individual C-peptide kinetics obtained after bolus intravenous injections of biosynthetic human C-peptide. First-phase insulin secretory responses to intravenous glucose and insulin secretion rates over a 24-h period on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and average ISRs over a glucose range between 5 and 9 mM were 61% lower than those in controls. In the controls, the beta cell was most sensitive to an increase in glucose at concentrations between 5.5 and 6.0 mM, whereas in the patients with GCK mutations the point of maximal responsiveness was increased to between 6.5 and 7.5 mM. Even mutations that resulted in mild impairment of in vitro enzyme activity were associated with a > 50% reduction in ISR. The responsiveness of the beta cell to glucose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During oscillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min for glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subjects with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-response curve to the right and reduced ability to entrain the ultradian oscillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships and define the alterations in beta-cell responsiveness that occur in subjects with GCK mutations.

Maturity-onset diabetes of the young (MODY), characterised by non-insulin-dependent diabetes mellitus (NIDDM) with an early age of onset, is a genetically heterogeneous disorder. In most MODY kindreds described in France, chronic hyperglycaemia is caused by mutations in the gene encoding pancreatic beta-cell and liver glucokinase (GCK). We here report the beta-cell secretory profiles of nine patients from four GCK-linked MODY kindreds. First-phase insulin secretion assessed by an intravenous glucose test was comparable in patients and seven controls. However, beta-cell secretory response to continuous glucose stimulus during a hyperglycaemic glucose clamp was significantly reduced: mean plasma insulin values of 12 (SD 7) vs 40 (11) mU/l (p = 0.0001) and mean plasma C-peptide values 1.20 (0.30) vs 2.61 (0.37) (p = 0.0001). This secretory profile is different from those for NIDDM with late age of onset or MODY not linked to GCK. Fasting plasma insulin and C-peptide in patients were inappropriately low in relation to concomitant plasma glucose level. Furthermore, during a hyperinsulinaemic euglycaemic clamp, endogenous insulin secretion at euglycaemia (5 mmol/l) was suppressed in patients but not in controls. These results suggest that mutant GCK may lead to chronic hyperglycaemia by raising the threshold of circulating glucose level which induces insulin secretion. These data provide the first demonstration of a primary pancreatic secretory defect associated with a form of NIDDM.

Glucose intolerance and noninsulin-dependent diabetes are commonly associated with hypertension. Epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. When hypertensive patients whether obese or of normal weight are compared with matched normotensive control subjects, an increased plasma insulin response to a glucose challenge is consistently observed. Studies using insulin glucose clamp techniques in combination with tracer glucose infusion and indirect calorimetry have demonstrated that the insulin resistance in hypertensive subjects is located in muscles and restricted to glycogen synthesis. The relations between hyperinsulinemia and blood pressure do not prove that the relationship is a causal one. However, at least four mechanisms may link hyperinsulinemia with hypertension: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport and proliferation of vascular smooth muscle cells. Diuretics and beta-blockers may enhance insulin resistance, which is not affected by calcium antagonists, but decreased by the ACE inhibitor captopril. Weight reduction and regular physical exercise can improve insulin sensitivity and decrease blood pressure values. These nonpharmacological interventions should be more strongly recommended to diabetic and nondiabetic hypertensive patients.

To assess the effect of Glipizide on glycaemic control and peripheral insulin sensitivity, 9 type 1 (insulin dependent) diabetic patients with normal BMI, mean age 42.1 +/- 11.0 years, diabetes duration 16.3 +/- 9.2 years were studied. They were treated by continuous subcutaneous insulin infusion for a mean duration of 32.2 +/- 11.0 months, they were in good glycaemic control (mean HbA1 7.9 +/- 1.2%, upper limit of normal value 7.5%). In a double blind randomized control study they were successively allocated for a three month period to 15 mg of Glipizide daily or a Placebo. At the end of each period the following parameters were recorded: HbA1, mean plasma glucose levels, daily insulin dosage: basal rate and pre prandial bolus, peripheral insulin sensitivity assessed by euglycaemic hyperinsulinic clamp technique, the addition of Glipizide did not induce any statistically significant modification of HbA1, glycaemic values, and daily insulin dosage: basal rate 18.2 +/- 8.7 vs. 17.9 +/- 7.3 IU/24 hours and pre prandial bolus 18.6 +/- 7.0 vs 17.6 +/- 6.3 IU/24 hours. During the glucose clamp, glucose uptake was similar under Glipizide or Placebo with the 3 levels of insulin infused. These results suggest that in type 1 diabetic patients the addition of Glipizide to insulin therapy does not alter glycaemic control and peripheral insulin sensitivity.

To explore simultaneously the effects on insulin secretion and on vascular tone of YC 170, a new dihydropyridine derivative calcium agonist, isolated perfused rat pancreases were studied for insulin output and for duodenopancreatic resistances before, during and after exposure to YC 170 10(-4) M (n = 15) or its solvent (n = 10). Although insulin was stimulated transiently during the five first minutes following addition of YC 170 (p less than 0.01) the integrated insulin output measured during the whole experiments was not different with YC 170 from that observed with solvent. Conversely, the initial duodenopancreatic resistances (22 +/- 4 mmHg.ml-1.min-1) rose progressively with YC 170 up to maximal values at the end of experiments (104 +/- 28 mmHg.ml-1.min-1; p less than 0.01); no significant variation occurred with solvent. Vascular and insulinotropic effects of YC 170 can be dissociated, suggesting variable abilities to promote calcium transport across membranes of smooth muscle cells and of pancreatic B-cells.

In small series of selected hypertensive diabetic patients the short-term benefit of antihypertensive treatments is well documented. The purpose of this study was to analyse the management of arterial hypertension in a cohort of 612 insulin-treated diabetic out-patients routinely and consecutively examined in a diabetologic clinic between January 1, 1985 and April 1, 1986. The prevalence of arterial hypertension (i.e. patients with blood pressure values greater than or equal to 160 and/or 95 mmHg or on antihypertensive treatment) was 38 per cent (232 patients). One hundred and eighty-two patients (29.7 per cent) received an antihypertensive treatment (one drug 78 per cent, two drugs 17 per cent, three drugs 5 per cent). In decreasing order of frequency these drugs were: beta-blockers, diuretics, central acting agents, angiotensin-converting enzyme inhibitors and calcium antagonists. In treated hypertensive diabetic patients the mean +/- SD systolic blood pressure (157.1 +/- 19.1 mmHg) and diastolic pressure (85.3 +/- 9.3 mmHg) remained higher than in patients without antihypertensive treatment (133.4 +/- 17.2 and 77.8 +/- 8.3 mmHg respectively). One hundred and forty-two diabetic patients still had blood pressure values greater than or equal to 160 and/or 95 mmHg during visits; 92 were on antihypertensive treatment, 50 were untreated. In hypertensive diabetic patients the mean total glycosylated haemoglobin (HbA1) level was higher than in normotensive diabetic patients (9 +/- 1.6 versus 8.6 +/- 1.8; P less than 0.05). Hypertensive insulin-treated diabetics are the most seriously ill patients, they are under inadequate care. Wrong choice of antihypertensive drugs, incorrect goals of blood pressure reduction, lack of information and education to improve compliance were the main reasons for the poor results of this study.

Insulin release is coupled with a calcium entry into the pancreatic B cells. The use of calcium-antagonists may eventually alter glucose homeostasis. To evaluate this possibility, nicardipine action was tested both in vitro and in vivo: 1. on insulin release and vascular resistances from isolated perfused rat pancreases; 2. on 7 hypertensive patients with an established glucose intolerance, during two oral glucose tolerance tests (OGTT) performed successively under placebo and nicardipine (90 mg daily) at a two-week interval. In vitro, the basal insulin release from isolated perfused rat pancreases (86 +/- 15 ng.min-1; n = 27; M +/- SE) was inhibited according to the nicardipine dose by the 5 th min. of infusion: 7.2 +/- 1.5 p.100 of the initial output at 10(-4) M (n = 6; p less than %.001); 33.4 +/- 2.7 p.100 at 10(-6) M (n = 6; p less than 0.001); 87.5 +/- 14.8 p.100 at 10(-8) M (n = 6; ns). The pancreatic vascular resistances declined significantly for the 3 doses, but no dose-response could be registered. In vivo, the mean arterial blood pressure was significantly reduced by nicardipine from 114 +/- 3 mmHg to 95 +/- 3 mmHg (p less than 0.001) without any significant alteration of either glucose tolerance (glycaemias at the 120 th min of OGTT: 9.2 +/- 1.1 mmol.l-1 vs 8.9 +/- 1.2 mmol.-1) or insulin peak: 70 +/- 20 micrograms U.ml-1 vs 67 +/- 22 microU.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Because Ca2+ antagonists may alter glucose homeostasis by blocking calcium entry into pancreatic beta-cells, this risk was evaluated for nicardipine, a new dihydropyridine derivative with vasodilatory effects. It was tested in vitro for its vascular and insulinotropic effects on isolated perfused rat pancreases. In vivo, an oral glucose tolerance test (OGTT) was conducted, and blood pressure was recorded in eight hypertensive patients with glucose intolerance who were given 90 mg/day nicardipine for 2 weeks in a single-blind placebo-controlled study. In vitro, insulin output was inhibited by 10(-4) M nicardipine but not by 10(-8) M and 10(-6) M, whereas significant changes in intrapancreatic perfusate flow indicated that vascular resistance was similarly reduced by all three concentrations. In vivo, blood pressure diminished significantly after nicardipine, but neither glucose tolerance nor insulin release was further impaired during OGTT. From these in vitro data and this short-term clinical follow-up, it is suggested that nicardipine reduces vascular tone at doses lower than those required to inhibit insulin secretion.

The relation between blood glucose control and erythrocyte adhesion to cultured human vascular endothelial cells was studied in 12 Type 1 (insulin-dependent) diabetic patients. Erythrocyte adhesion was measured before, 8 days and 6 weeks after continuous subcutaneous insulin infusion (CSII). Compared to controls, erythrocyte adhesion expressed as an adhesion ratio was increased in 10 diabetic patients at the first examination (adhesion ratio greater than 1.52). After 8 days, adhesion ratio was normalized in 5 patients. After 6 weeks, adhesion ratio was normal in 7 patients and significantly lower in the group of 12 patients (p less than 0.01). The adhesion ratio was significantly correlated with glycosylated haemoglobin values (p less than 0.001). Insulin did not directly affect erythrocyte adhesion. Adequate insulin treatment modifies erythrocyte adhesion through a metabolic effect which needs longer than 1 week to be effective.

In diabetic patients, it has been suggested that angiotensin converting enzyme inhibitors may be associated with unexplained hypoglycaemic episodes. Such a side effect may limit the use of these drugs in diabetic hypertensive patients. Ten insulin-dependent diabetic patients mean age 38.4 +/- 13.1 years, mean diabetes duration 10.3 +/- 6.6 years (m +/- SD) were selected on the basis of good glycaemic control: HbA1: 7.6 +/- 0.9 per cent (upper limit of normal value less than 7.5 per cent) on continuous subcutaneous insulin infusion. In a double blind study, they were randomly and successively allocated for a 3 months period to enalapril 20 mg daily or placebo. Before treatment, after enalapril and placebo, mean blood glucose values, HbA1, daily insulin dosage were recorded as well as the number of clinical and biological (less than 3 mmol/l) hypoglycaemic episodes. Peripheral insulin sensitivity was assessed by euglycaemic insulin clamp technique. Compared to placebo, enalapril did not induce any modification of daily insulin dosage, glycaemic control. The incidence of hypoglycaemic episodes was similar. Neither peripheral insulin sensitivity was modified by enalapril. In the conditions of this study, enalapril did not interfere with glycaemic control in insulin-dependent diabetics in good metabolic control.

Combined continuous subcutaneous insulin infusion (CSII) and metformin (M) was tested in 10 overweighted insulin requiring diabetic patients (body mass index 27.9 +/- 4.9 kg/m2). They were still poorly controlled (HbA1 9.6 +/- 0.8%) despite large doses of lente insulin (Novo) (51.7 +/- 19.6 IU/24 h) injected once daily. With CSII after two weeks on placebo (P) they were enrolled in a randomized double blind cross-over trial with two successive one month periods of M (2550 mg/day) or P. At the end of the two-weeks period CSII--initial P, the daily regular insulin requirement decreased significantly (40.1 +/- 18.1). During M and P body weight and HbA1 were unchanged (respectively 28.6 +/- 6.0 vs 29.0 +/- 59 kg/m2 and 7.7 +/- 1.1 vs 7.7 +/- 0.8%). With M daily insulin requirements decreased significantly (32.0 +/- 16.8 vs 38.4 +/- 18.2 IU, p less than 0.05). During test-meals, M compared to placebo also reduced peripheral free insulin concentrations (-24.9 +/- 26.0%) while plasma glucose and C peptide remained comparable. In the conditions of this study, combined CSII and M reduced the insulin resistance observed in overweighted insulin requiring diabetic patients.

A 1.6 mg dose of the specific opiate antagonist naloxone was administered to normal volunteers, either separately or in conjunction with insulin-induce hypoglycemia, in order to study the possible mediation by opioid peptides of the release of adrenocorticotrophin (ACTH), lipotropins (LPH), human growth hormone (GH) and prolactin (PRL). Administered separately, naloxone was associated with a significant fall in PRL levels (p less than 0.01), a significant and unexpected rise in GH levels (p less than 0.02), and a suppression of the circadian decrease of ACTH and LPH levels. The association of naloxone with insulin-induced hypoglycemia significantly reduced the PRL peak (p less than 0.05), did not affect the rise of GH and lowered the ACTH peak, without altering the LPH peak. These data suggest the existence of a positive opioid tone to PRL secretion, as well as an opioid peptide role in the PRL response to hypoglycemia. They argue against the likelihood of an opioid pathway in the GH response to hypoglycemia. Furthermore, the data favor a paradoxical effect of naloxone on ACTH release during insulin-induced hypoglycemia.

Eighty insulin treated diabetics from North or West Africa were interviewed and compared to 80 French controls matched for sex, age and duration of insulin-therapy. Modalities and access to medical care in a specialized clinic were studied. African people were predominantly blue collar workers (49%) and French people employees (70%). The percentage of unemployed people was similar. Africans performed blood glucose self testing less frequently (35.5% vs 60.5%). Only 40% (vs 75%) participated in specific educational activities because 40% of the migrants did not read French. Despite insulin treatment being similar, metabolic control was worse among migrants (HbA1: 10.5 +/- 2.4 vs 9.3% +/- 1.9; p less than 0.01). In migrants, there was an increased prevalence of degenerative complications which did not reach statistical significance. Three parameters may explain these differences: less strict follow-up, poorer knowledge, lower socioeconomic status.

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Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)