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P Passa

Publications and source records attributed to P Passa.

At least 73 records · Page 4Linked to original sources
PubMed1994

Arginine-induced insulin release in glucokinase-deficient subjects.

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.

Adolescent↗
PubMed1994

Immunoradiometric assay of human intact proinsulin applied to patients with type 2 diabetes, impaired glucose tolerance, and hyperandrogenism.

We describe an immunoradiometric assay for human intact proinsulin in serum. In this method, one monoclonal antibody, coated onto polyacrylamide beads, cross-reacts with proinsulins and insulin. A sandwich is formed with intact proinsulin, split (65-66) proinsulin, and des (64-65) proinsulin binding with an 125I-labeled monoclonal antibody specific for an epitope at the intact B-C junction of proinsulin. Because split (65-66) and des (64-65) proinsulin concentrations are very low in serum, this assay essentially measures intact proinsulin. When we used 1-mL serum samples, the mean detection limit was 0.4 pmol/L. Mean proinsulin concentrations (pmol/L) were 3.4 (range 1-9.1) in healthy fasting subjects, 28.5 (9.7-101) in patients with type 2 diabetes (treated with metformin and sulfonylureas), 5.0 (1.6-9.3) in women with hyperandrogenism and normal insulinemia, 10.3 (2.6-36) in women with hyperandrogenism and hyperinsulinemia, and 8.5 (4.8-21.3) in patients with impaired glucose tolerance.

Adult↗
PubMed1993

Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus.

BACKGROUND AND METHODS: Non-insulin-dependent diabetes mellitus (NIDDM) is a genetically heterogeneous disorder. Maturity-onset diabetes of the young, a form of NIDDM with an early age of onset and autosomal dominant inheritance, can result from mutations in glucokinase, a key enzyme of glucose metabolism in beta cells and the liver. We studied 32 French families with maturity-onset diabetes of the young as well as 21 families with late-onset NIDDM to determine the frequency and clinical features of mutations of glucokinase. Fasting plasma glucose concentrations and oral glucose-tolerance tests were used to determine metabolic status. DNA was isolated from lymphocytes, and DNA polymorphisms in the glucokinase gene were tested for linkage with diabetes. Individual exons of the glucokinase gene from one affected member in each family were amplified by the polymerase chain reaction and screened for mutations by analysis of the conformation-dependent polymorphisms of single-stranded DNA and by DNA sequencing. RESULTS: We found substantial evidence of linkage between the glucokinase locus and maturity-onset diabetes of the young but not between this locus and late-onset NIDDM: Sixteen mutations were identified in 18 of the 32 families with maturity-onset diabetes of the young, but none were found in families with late-onset NIDDM: They included 10 mutations that resulted in an amino acid substitution, 3 that resulted in the synthesis of a truncated protein, and 3 that affected RNA processing. The affected subjects with glucokinase mutations usually had mild hyperglycemia that began during childhood, whereas in subjects with maturity-onset diabetes of the young not due to glucokinase mutations, hyperglycemia usually appeared after puberty. CONCLUSIONS: Mutations in glucokinase are the primary cause of hyperglycemia in a substantial fraction of French patients with maturity-onset diabetes of the young and result in a relatively mild form of NIDDM that can be diagnosed in childhood.

Adult↗
PubMed1993

Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young.

Missense and nonsense mutations in the glucokinase gene have recently been shown to result in maturity-onset diabetes of the young (MODY), a subtype of non-insulin-dependent diabetes mellitus with early age of onset. Glucokinase catalyzes the formation of glucose-6-phosphate and is involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Nucleotide sequence analysis of exon 4 and its flanking intronic regions of the glucokinase gene, in four hyperglycemic individuals of a MODY family, revealed a deletion of 15 base pairs, which removed the t of the gt in the donor splice site of intron 4, and the following 14 base pairs. This deletion resulted in two aberrant transcripts, which were analyzed by reverse transcription of RNA from lymphoblastoid cells obtained from a diabetic patient. In one of the abnormal transcripts, exon 5 is missing, while in the other, the activation of a cryptic splice site leads to the removal of the last eight codons of exon 4. This intronic deletion in a donor splice site seems to cause a more severe form of glucose intolerance, compared with point mutations described in glucokinase. This might be due to a more pronounced effect on insulin secretion.

Adult↗
PubMed1993

Linkage analysis and molecular scanning of glucokinase gene in NIDDM families.

Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.

Adolescent↗
PubMed1993

Lipoprotein(a) in diabetic patients and normoglycemic relatives in familial NIDDM.

OBJECTIVE: To compare lipoprotein(a) levels in diabetic patients and normoglycemic relatives in familial NIDDM and to assess whether Lp(a) is a risk factor for myocardial infarction in this population. RESEARCH DESIGN AND METHODS: We compared 577 patients and 261 normoglycemic relatives from 189 NIDDM multiplex families with 49 unrelated healthy individuals. Of the 577, 23 patients with previously documented myocardial infarction were further analyzed as a separate group. RESULTS: Lp(a) concentrations in diabetic patients, normoglycemic relatives, and the control group were not significantly different. Variance of Lp(a) in a given individual could not be accounted for by any clinical or biological parameter, but was strongly related to the mean Lp(a) value in his or her family. Diabetic patients with previous myocardial infarction (and their relatives) had significantly higher levels of Lp(a) than patients without coronary heart disease complaints. CONCLUSIONS: Lp(a) concentration in familial NIDDM was not related to the degree of glucose intolerance, but presented a strong familial aggregation. High Lp(a) levels seem to be an independent risk factor for myocardial infarction in this NIDDM cohort.

Adult↗
PubMed1993

Insulin resistance and hypertension.

In non obese, nondiabetic patients, essential hypertension is associated with an insulin resistance that is peripheral in location and metabolically selective. The correlations between hyperinsulinemia, insulin resistance and blood pressure values do not prove that the relationship is a causal one. Different data support this hypothesis, however, the demonstration in humans that insulin resistance play a central role in the development of essential hypertension and coronary heart disease is still lacking. The relative current failure of coronary heart disease prevention in hypertensive patients may be related to the metabolic side effects of diuretics and beta-blockers. These drugs increase insulin resistance and lipid disorders. Angiotensin-converting enzyme inhibitors and calcium antagonists do not decrease insulin sensitivity neither alter lipid profile. Angiotensin-converting enzyme inhibitors and calcium antagonists have significantly improve compliance to pharmacological therapy, however their use has been associated with a dramatic cost increase and we do not yet know if they would reduce morbidity and mortality as well as or better than older and cheaper antihypertensive agents. Nonpharmacological interventions are usually very effective to reduce insulin resistance and the different cardiovascular risk factors present in most hypertensive patients. To improve patient's compliance to diet and regular exercise we have to develop new strategies.

Antihypertensive Agents↗
PubMed1993

[Hypertension and hyperinsulinism in non-insulin-dependent diabetes. A study of 230 patients].

This study was designed to analyse the relationship between hypertension and hyperinsulinemia in type 2 diabetes (NIDDM). Two hundred and thirty male type 2 diabetic patients consecutively hospitalized from January to June 1991 were included in the study. The following parameters wer recorded: age, known duration of diabetes, BMI (kg/m2), waist to hip ratio (WHR), HbAlc, triglycerides, total and HDL cholesterol, fasting plasma insulin level (RIA determination), insulin-resistance assessment (fasting insulinemia/fasting glycemia), hypertension (BP > or = 160 and/or 95 mmHg or presence of antihypertensive treatment), parental history and hypertension, modalities of treatment of diabetes. The distribution of fasting insulin concentrations resulted in a skewed curve: mean +/- SD: 16.5 +/- 10.9, median (ranges): 13.0 (9.5-19). Hyperinsulinemia was defined as fasting insulin level > 22 mUI/ml (value corresponding to the last quintile of distribution of insulinemia in this population and to the extreme value of insulinemia in a cohort of 100 control subjects). Sixty five patients were on diet alone, 45 had biguanide alone, 39 had sulfamide alone and 81 had both biguanide and sulfamide medications. The prevalence of hypertension was 44% (n = 102). Patients with hypertension, compared to those without, had significant (p < 0.05) higher values for age, duration of diabetes, BMI, WHR, prevalence of hyperinsulinemia and plasma insulin levels. These two groups were similar as regards HbAlc, insulin resistance assessment, treatment of diabetes and parental history of hypertension. Patients with hyperinsulinemia were younger (p < 0.03), had higher prevalence of hypertension (p < 0.04), higher values for triglycerides (p 0.01) and lower values for HDL cholesterol (p < 0.003) than those without hyperinsulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

[Cost of the treatments of arterial hypertension associated with diabetes].

In insulin-dependent and non insulin-dependent diabetic patients, the treatment of a modest increase in blood pressure values has been proved effective in reducing the incidence and in improving the evolution of various locations of diabetic angiopathy. This beneficial effect is associated with a cost which can be evaluated by the analysis of IMS and DOREMA data. In France, the evolution of the sales of antihypertensive agents in diabetic patients increased from 117 MF in 1980 to 784 MF in 1991. This dramatic increase is mainly related to the prescription of new antihypertensive agents: calcium antagonists and ACE inhibitors. From 1980 to 1991, the evolution of antihypertensive agent's sales was more important in diabetic patients than in the general population. In 1991, the total cost of antidiabetic treatment: insulin, antidiabetic oral agents and strips for capillary blood glucose monitoring was about 1,100 MF, quite similar to the cost of antihypertensive and hypolipidemic agents used in the same patients.

Antihypertensive Agents↗
PubMed1992

Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young.

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.

Adolescent↗
PubMed1992

Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) which is characterized by an early age at onset and an autosomal dominant mode of inheritance. Except for these features, the clinical characteristics of patients with MODY are similar to those with the more common late-onset form(s) of NIDDM. Previously we observed tight linkage between DNA polymorphisms in the glucokinase gene on the short arm of chromosome 7 and NIDDM in a cohort of sixteen French families having MODY. Glucokinase is an enzyme that catalyses the formation of glucose-6-phosphate from glucose and may be involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Because the glucokinase gene was a candidate for the site of the genetic lesion in these families, we scanned this gene for mutations. Here we report the identification of a nonsense mutation in the gene encoding glucokinase and its linkage with early-onset diabetes in one family. To our knowledge, this result is the first evidence implicating a mutation in a gene involved in glucose metabolism in the pathogenesis of NIDDM.

Base Sequence↗
PubMed1992

Hyperinsulinemia, insulin resistance and essential hypertension.

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.

Antihypertensive Agents↗
PubMed1992

Does antihypertensive treatment prevent progression of microalbuminuria to overt proteinuria in insulin-dependent diabetic patients?

Prospective studies in insulin-dependent diabetic patients have shown that microalbuminuria is a strong predictor of clinical nephropathy. Because this syndrome is associated with a dramatic excess in mortality, different types of intervention have been proposed for insulin-dependent diabetic patients with microalbuminuria to prevent or postpone clinical nephropathy. The effects of antihypertensive treatment are being extensively investigated. Beta-blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors have proved effective in reducing albumin excretion and postponing overt proteinuria in hypertensive and normotensive insulin-dependent diabetic patients with microalbuminuria. However, many problems remain to be solved. A decrease in albumin excretion may not be an adequate endpoint for intervention trials, because it has been shown that patients with normal albumin excretion can develop diabetic nephropathy lesions, whereas patients with microalbuminuria alone may have little or no pathology. The patients included in these trials all had incipient diabetic nephropathy but exhibited different functional, and probably morphological, forms of the disease. For insulin-dependent diabetic patients with microalbuminuria, the real aim of antihypertensive treatment is not to reduce urinary albumin excretion or to prevent its progression but to preserve renal function and to reduce the incidence of premature cardiovascular deaths. To achieve this, we have to improve our knowledge of the natural history of the early pathology of diabetic nephropathy and of the mechanisms of action of antihypertensive treatment. New large-scale intervention trials will have to be designed in which the patients will have to be carefully characterized on the basis of functional and morphological data.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed1992

Non-invasive identification of severe coronary artery disease in patients with long-standing diabetes mellitus.

OBJECTIVES: To detect severe coronary artery disease in asymptomatic middle-aged diabetic patients exposed to coronary artery disease risk factors. PATIENTS AND METHODS: Forty-four middle-aged patients (30 to 65 years of age) with a known duration of diabetes exceeding 10 years and at least one additional cardiovascular risk factor were studied. Patients were free of anginal chest pain and had a normal 12-lead ECG at rest. All patients underwent 24-hour ambulatory ECG, maximal bicycle exercise electrocardiography and intravenous dipyridamole thallium myocardial scintigraphy. If one of these 3 non-invasive tests revealed signs of myocardial ischaemia, a coronary angiography was performed. RESULTS: Non-invasive investigation yielded the diagnosis of myocardial ischaemia in 9/44 patients (20%). Six of the 9 patients had significant coronary artery stenoses (> 70% narrowing) and 5 exhibited severe triple-vessel disease. With dipyridamole thallium scintigraphy, the positive predictive value for diagnosis of coronary artery disease was optimal. CONCLUSION: In diabetic patients with additional coronary risk factors, periodical thorough clinical examination and resting ECG may fail to detect severe coronary disease. More sophisticated cardiovascular non-invasive tests should then be proposed as part of the periodical care of these patients.

Coronary Angiography↗
PubMed1992

[Hypertension associated with diabetes: inquiry into the attitudes and behaviors of French physicians].

In order to assess the prevalence of arterial hypertension, diabetes mellitus, and of the association of both diseases, and furthermore, to underline the behaviours and feelings of French physicians in front of these combined diseases, a survey has been undertaken by the SOFRES Medical institute and by Laboratoires Hoechst, which involved 304 physicians in private practice and 67 hospital doctors. After face-to-face interviews, each participant had to fill up a questionnaire dealing with his general feelings and attitudes, and then completed 2 case record forms (5 cases for hospital doctors) from their last patients who presented with hypertension and diabetes mellitus. All these informations have allowed us to describe their behaviours. The 304 physicians have been selected with a regional stratification by a random survey quota method that gave a valid sample from the French medical population: 213 general practitioners (GPs), 67 cardiologists, 24 endocrinologists have been involved in the survey. They have been able to observe 149 hypertensive insulin-dependent diabetic patients and 470 hypertensive non insulin-dependent diabetic patients (respectively 24% and 76%). In addition, 67 hospital doctors (32 cardiologists, 17 diabetologists, 18 nephrologists) have been involved and have filled 255 case record forms (120 insulin-dependent and 135 non insulin-dependent diabetic patients). The association between hypertension and diabetes mellitus is very common: 55% out of the diabetic patients treated by GPs presented with hypertension, 20% out of the hypertensive patients presented with diabetes mellitus. The discovery of hypertension is usually followed by the discovery of non insulin-dependent diabetes mellitus. The opposite feature is observed for the insulin-dependent diabetic patients. The majority of the doctors feels that the cardiovascular prognosis of the association is worse than each single disease. The level of blood pressure that is suitable to start an antihypertensive treatment in hypertensive insulin-dependent and non insulin-dependent diabetic patients is generally lower than for non diabetic hypertensive patients, especially for the diabetologists. Concerning antihypertensive treatments, discrepancies have been observed in between feelings and behaviours of physicians. The class of drug that is thought to be used is obviously different from the one which is really used: angiotensin-converting enzyme inhibitors and calcium antagonists, two rather new classes of drugs are popular while classical classes of antihypertensive agents like diuretics and betablockers are still commonly used. Non pharmacological interventions which are useful for both the treatment of hypertension and diabetes mellitus are not commonly recommended by GPs and specialists.

Cardiology↗