Obesity effect on newly diagnosed and recurrent post-ablation atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The role of overweight and obesity in the development of atrial fibrillation (AF) is well established; however, the differential effect on the occurrence and recurrence of AF remains uncertain. The aim of this review is to compare the effect of underweight and varying degrees of obesity on onset of AF and in recurrent post-ablation AF, and, when possible, in relation to sex. METHODS: A systematic literature search was conducted in PubMed, Embase, and Cochrane Library from inception to January 31, 2023. Studies reporting frequency of newly-diagnosed AF and of recurrent post-ablation AF in different BMI categories, were included. 3400 records were screened and 50 met the inclusion criteria. Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were extracted from the manuscripts and were analyzed using a random effect model. The outcome was the occurrence of AF in population studies and in patients undergoing ablation. RESULTS: Data from 50 studies were collected, of which 27 for newly-diagnosed AF and 23 for recurrent post-ablation AF, for a total of 15,134,939 patients, of which 15,115,181 in studies on newly-diagnosed AF and 19,758 in studies on recurrent post-ablation AF. Compared to normal weight, the increase in AF was significant (p < 0.01) for overweight, obese, and morbidly obese patients for newly-diagnosed AF, and for obese and morbidly obese patients for recurrent post-ablation AF. Newly-diagnosed AF was more frequent in obese female than obese male patients. CONCLUSION: The effect of increased BMI was greater on the onset of AF, and obese women were more affected than men.

Subcutaneous fat loss is greater than visceral fat loss with diet and exercise, weight-loss promoting drugs and bariatric surgery: a critical review and meta-analysis.

Aim of this review is to compare visceral and subcutaneous fat loss with all available strategies (diet and exercise, weight-loss promoting agents and bariatric surgery). Eighty-nine studies, all full papers, were analyzed to evaluate visceral and subcutaneous fat changes, measured through ultrasound, computerized tomography, magnetic resonance imaging and expressed as thickness, weight, area and volume. Studies were included in a meta-analysis (random-effects model). Intervention effect (absolute and percent changes of visceral and subcutaneous fat) was expressed as standardized mean differences, with 95% confidence intervals. Publication bias was formally assessed. The result was that subcutaneous fat was greater than visceral fat when measured as area, volume and weight, not as thickness; decrease of subcutaneous fat was greater than visceral fat when measured as area, volume and weight, not as thickness; percent decrease of visceral fat was always greater than percent decrease of subcutaneous fat, with no differences between different strategies. No intervention preferentially targets visceral fat. Basal visceral fat depots are smaller than basal subcutaneous fat depots. Visceral fat loss is linked to subcutaneous fat loss. With all strategies, percent decrease of visceral fat prevails on subcutaneous fat loss.

Bariatric surgery and prevention of cardiovascular events and mortality in morbid obesity: mechanisms of action and choice of surgery.

AIMS: Obesity is associated with increased cardiovascular (CV) morbidity and mortality. Weight loss improves several risk factors for CV diseases, but anti-obesity medications and lifestyle interventions have failed to modify primary CV endpoints. This paper reviews bariatric surgery in prevention of CV diseases and CV mortality, and analyzes the possible mechanisms involved. DATA SYNTHESIS: In morbidly obese patients bariatric surgery results in stable weight loss and in long-term reduction in the prevalence and incidence of obesity-related comorbidities; controlled trials have shown superiority of bariatric surgery over medical therapy in inducing significant weight loss and improvement of CV risk factors. Bariatric surgery induces several metabolic improvements (resolution of type 2 diabetes mellitus, improvement of lipid metabolism and of insulin resistance, reduction of visceral fat, of subclinical endothelial dysfunction and inflammation), and functional improvements (reduction of hypertension, of sympathetic overactivity, of left and right ventricular hypertrophy), which can explain the protective effect towards CV disease. CONCLUSIONS: Reduction of CV diseases is mediated by the pleiotropic effects of weight loss through surgery. Available data do not allow conclusions on the comparative efficacy of different surgical techniques; the choice of the surgical technique for a single patient remains an open question, and it is likely that the degree of prevention of CV diseases depends, among other factors, on the baseline conditions of patients. Large prospective studies are needed to address this issue in morbidly obese patients.

Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies.

AIM: Different intervention strategies can prevent type 2 diabetes (T2DM). Aim of the present systematic review and meta-analysis was to evaluate the effectiveness of different strategies. METHODS: Studies were grouped into 15 different strategies: 1: diet plus physical activity; 2: physical activity; 3-6: anti-diabetic drugs [glitazones, metformin, beta-cell stimulating drugs (sulphanylureas, glinides), alfa-glucosidase inhibitors]; 7-8: cardiovascular drugs (ACE inhibitors, ARB, calcium antagonists); 9-14 [diets, lipid-affecting drugs (orlistat, bezafibrate), vitamins, micronutrients, estrogens, alcohol, coffee]; 15: bariatric surgery. Only controlled studies were included in the analysis, whether randomized, non-randomized, observational studies, whether primarily designed to assess incident cases of diabetes, or performed with other purposes, such as control of hypertension, of ischemic heart disease or prevention of cardiovascular events. Appropriate methodology [preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement] was used. Seventy-one studies (490 813 subjects), published as full papers, were analysed to identify predictors of new cases of T2DM, and were included in a meta-analysis (random-effects model) to study the effect of different strategies. Intervention effect (new cases of diabetes) was expressed as odds ratio (OR), with 95% confidence intervals (C.I.s). Publication bias was formally assessed. RESULTS: Body mass index was in the overweight range for 13 groups, obese or morbidly obese in lipid-affecting drugs and in bariatric surgery. Non-surgical strategies, except for beta-cell stimulating drugs, estrogens and vitamins, were able to prevent T2DM, with different effectiveness, from 0.37 (C.I. 0.26-0.52) to 0.85 (C.I. 0.77-0.93); the most effective strategy was bariatric surgery in morbidly obese subjects [0.16 (C.I. 0.11,0.24)]. At meta-regression analysis, age of subjects and amount of weight lost were associated with effectiveness of intervention. CONCLUSIONS: These data indicate that several strategies prevent T2DM, making it possible to make a choice for the individual subject.

Metabolic control and risk of hypoglycaemia during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis.

AIM: Aim of this study was to analyse clinical correlates of HbA1c, and of overall, nocturnal, and severe hypoglycaemia, through direct-weighted regressions, as well as the effect of different insulin regimens and insulin analogues, through meta-analysis. METHODS: Appropriate methodology (PRISMA statement) was used. Sixty-seven randomized studies, published as full papers were analysed to identify predictors of both HbA1c and hypoglycaemia; studies were included in a meta-analysis to study the effect of different insulin regimens or insulin analogues on HbA1c and hypoglycaemia during the first year of insulin treatment in type 2 diabetes patients. RESULTS: Final HbA1c, change of HbA1c, hypoglycaemia, nocturnal hypoglycaemia and severe hypoglycaemia were associated with intensity of treatment. Final HbA1c was higher with basal than with twice-a-day or prandial, and with twice-a-day than with prandial regimen, with opposite figures for hypoglycaemia. Within basal regimens, detemir and glargine were similar to NPH insulin on HbA1c, with less hypoglycaemia and nocturnal hypoglycaemia; within prandial regimens, new analogues were more effective than regular insulin on HbA1c, and induced less hypoglycaemia. The effect of glargine on HbA1c and on hypoglycaemia vanished with increasing number of insulin injections. CONCLUSION: Metabolic control and hypoglycaemia are associated with intensity of treatment. Basal regimens have a reduced effect on metabolic control, but are associated with lower frequency of hypoglycaemia. Newer analogues, short- and long-acting, yield better control and less hypoglycaemia than older analogues.

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance.

AIMS/HYPOTHESIS: We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. METHODS: Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. RESULTS: Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. CONCLUSIONS/INTERPRETATION: Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.

Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis.

AIM: This systematic review and meta-analysis was to evaluate the body weight increase and its clinical correlates, through direct weighted regressions, as well as the effect of different insulin regimens and insulin analogues, through meta-analysis. METHODS: Appropriate methodology according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was adhered to. Forty-six randomized studies, published as full papers, reporting the effect of insulin treatment on change in body weight were identified, and used to identify predictors of weight change; studies were included in a meta-analysis to study the effect of different insulin regimens or insulin analogues on weight change. RESULTS: Intensity of treatment [aim of study (fasting blood glucose, mg/dl), dose of insulin, final HbA1c, change of HbA1c and frequency of hypoglycaemia] was significantly associated with body weight increase, with small differences between basal versus twice-a-day and prandial regimen. At meta-analysis, body weight increase was lower with basal regimen than with twice-a-day regimen and than with a prandial regimen. Within all regimens, body weight increase was lower with detemir than with NPH, with no difference between glargine and NPH; only two studies directly compared detemir and glargine, indicating lower weight gain with the former insulin. Within twice-a-day regimens and within prandial regimens, comparison was between newer analogues and older drugs, with no significant difference in body weight increase. CONCLUSION: Body weight increase during the first year of insulin treatment is associated with the intensity of treatment; body weight increase also depends on the insulin regimen applied.

Comparison of insulin lispro protamine suspension versus insulin glargine once daily in basal-bolus therapies with insulin lispro in type 2 diabetes patients: a prospective randomized open-label trial.

AIMS: To compare the efficacy and safety of insulin lispro protamine suspension (ILPS) versus insulin glargine once daily in a basal-bolus regimen in type 2 diabetes mellitus (T2DM) patients. METHODS: Three hundred eighty-three insulin-treated patients were randomized to either ILPS plus lispro or glargine plus lispro in this open-label 24-week European study. Insulin doses were titrated to predefined blood glucose (BG) targets. Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of the 95% confidence interval (CI) for the change of HbA1c from baseline to week 24 (adjusted for country and baseline HbA1c) with the non-inferiority margin of 0.4%. Secondary endpoints included HbA1c categories, BG profiles, insulin doses, hypoglycaemic episodes, adverse events and vital signs. RESULTS: Non-inferiority of ILPS versus glargine in the change of HbA1c from baseline was shown: least-square mean between-treatment difference (95% CI) was 0.1% (-0.11; 0.31). Mean changes at week 24 were -1.05% (ILPS) and -1.20% (glargine). HbA1c <7.0% was achieved by 21.7 versus 29.4% of patients. Mean basal/mealtime insulin doses at week 24 were 29.6/36.2 IU/day (ILPS) versus 32.8/42.2 IU/day (glargine); the difference was not statistically significant for total dose (p = 0.7). In both groups, 56.1/25.7% versus 63.6/19.3% of patients experienced any/nocturnal hypoglycaemia (p = 0.2 for both). No relevant differences were noted in any other variables. CONCLUSIONS: A basal-bolus regimen with ILPS once daily resulted in non-inferior glycaemic control compared to a similar regimen with glargine, without statistically significant or clinically relevant differences in hypoglycaemia. ILPS-based regimens can be considered an alternative to basal-bolus regimens with glargine for T2DM patients.

Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity.

BACKGROUND AND AIMS: Several mechanisms are probably involved in obesity-related hypertension. This study was aimed to investigate the effect of significant weight loss on blood pressure and plasma renin activity (PRA) and aldosterone levels, other then on metabolic profile, in normotensive and hypertensive obese subjects. METHODS AND RESULTS: Forty hypertensive and 55 normotensive obese subjects were studied under basal conditions and again 1 year after significant weight loss obtained through laparoscopic adjustable gastric banding (LAGB). Weight, waist circumference, blood glucose, insulin, electrolytes (Na and K), lipids and supine and upright PRA and aldosterone were evaluated. All parameters evaluated improved, except for total cholesterol, and electrolytes that did not change. Blood pressure decreased in hypertensive subjects, with a concordant decrease in PRA and supine aldosterone levels, not observed in normotensive patients. CONCLUSION: Weight loss is associated with reduction of blood pressure and of PRA and aldosterone levels in obese hypertensive subjects.

Bariatric surgery in obesity: changes of glucose and lipid metabolism correlate with changes of fat mass.

BACKGROUND AND AIM: Bariatric surgery induces significant weight loss and improves glucose metabolism in obese patients (BMI>35 kg/m(2)). Our aim was to compare restrictive (LAGB, laparoscopic gastric banding) and malabsorptive approaches (BIBP, biliary-intestinal bypass) on the loss of fat-free mass (FFM), fat mass (FM), and on changes of glucose and lipid metabolism. METHODS AND RESULTS: Body composition (bio-impedance analysis, BIA), blood glucose (BG), insulin, triglycerides, total- and HDL-cholesterol, liver enzymes (AST and ALT) were measured at baseline and 1 year after surgery in patients undergoing LAGB, BIBP, and in diet-treated control patients. In the main study, with patients matched for initial BMI (43-55 kg/m(2), LAGB=24, BIBP=12, controls=6), decreases of BMI, FM, BG and cholesterol were greater in patients with BIBP than with LAGB (p<0.01), while decreases of FFM, insulin, HOMA-IR and triglycerides were similar. No effects on BMI, FM, FFM, BG, insulin, HOMA-IR or cholesterol were observed in the control patients. Decreases of BG, insulin, HOMA-IR, cholesterol and triglycerides correlated with FM but not with FFM decrease. Similar results were obtained in an additional study in patients with a different initial BMI (LAGB=25, BIBP=6, controls=24) and when considering all subjects together. A decrease of liver enzymes (ALT) was greater with LAGB than with BIBP, and HDL-cholesterol increased with LAGB and decreased with BIBP. CONCLUSION: BMI, FM, BG and cholesterol decrease more with malabsorptive than with restrictive surgery, while FFM, insulin, HOMA-IR and triglycerides decrease in a similar way. FFM loss is of low entity. Changes of glucose and lipid metabolism are proportional to a decrease of fat mass but not of fat-free mass.

Usefulness of chemical-shift MRI in discriminating increased liver echogenicity in glycogenosis.

BACKGROUND: Glycogen storage diseases are inherited defects which cause accumulation of glycogen in the tissues. Hepatic steatosis is defined as accumulation of fat within hepatocytes. On sonography, liver shows increased echogenicity both in glycogen storage diseases and steatosis. Liver hyperechogenicity in glycogen storage diseases may depend on accumulation of glycogen and/or fat. Chemical-shift magnetic resonance imaging can discriminate tissues only containing water from those containing both fat and water. AIM: The primary aim of the present study was to evaluate the usefulness of liver chemical-shift magnetic resonance imaging for detecting liver steatosis in patients with metabolic impairment due to glycogen storage diseases. SUBJECTS: Twelve patients with type I (n=8) or type III (n=4) glycogen storage diseases were studied and compared to 12 obese-overweight subjects with known liver steatosis. As control group 12 lean normal voluntary subjects were recruited. METHODS: Liver was evaluated by sonography and chemical-shift magnetic resonance imaging to calculate hepatic fat fraction. RESULTS: A significant difference in echogenicity between patients with glycogen storage diseases and normal subjects was observed (p<0.05), while this difference was not present between overweight-obese and glycogen storage diseases patients. On the contrary, fat fraction was similar between glycogen storage diseases patients and normal subjects and different between glycogen storage diseases patients and overweight-obese (p<0.05). CONCLUSION: The present data suggest that chemical-shift magnetic resonance imaging may exclude fat deposition as a cause of liver hyperechogenicity in subjects with glycogen storage diseases.

Bariatric surgery and diabetic retinopathy: a systematic review and meta-analysis of controlled clinical studies.

BACKGROUND: Uncontrolled studies have indicated appearance or progression of diabetic retinopathy in obese diabetic patients after bariatric surgery. The aim of this systematic review and meta-analysis was to compare the rate of appearance, as well as progression or regression of diabetic retinopathy in studies comparing medical and surgical treatment of obese type 2 diabetes. METHODS AND FINDINGS: Intervention effect (new cases of retinopathy, and cases with any change of diabetic retinopathy score) was expressed as odds ratio (OR), with 95% confidence intervals (CIs); change of diabetic retinopathy score was expressed as standardized mean difference (SMD), with 95% CIs. Meta-analyses were performed by a random-effects model according to DerSimonian and Laird. Heterogeneity was assessed through Q and I2 statistics for each comparison, and potential sources of heterogeneity were discussed where appropriate. Appropriate methodology [preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement] was used. Seven studies were analyzed, and incident cases of retinopathy were fewer with bariatric surgery than with medical treatment; change of retinopathy score (three studies) was not different, while only two studies were available on numbers of patients showing progression or regression of retinopathy. Heterogeneity was not significant, and publication bias was not present. CONCLUSIONS: Bariatric surgery seems to prevent new cases of diabetic retinopathy, but available studies are not sufficient to support progression or regression of retinopathy. Further studies are needed to draw firm conclusions on the effect of bariatric surgery on diabetic retinopathy.

Prevalence of erectile dysfunction in thyroid disorders: comparison with control subjects and with obese and diabetic patients.

Diagnosis of erectile dysfunction (ED) requires anamnestic investigation, being rarely spontaneously declared by patients. ED occurs frequently in diabetes mellitus, and anecdotal evidence suggests that ED occurs in obesity and in hypothyroidism. The aim of this study was to evaluate the prevalence of ED in patients affected by thyroid disorders (hypothyroidism and hyperthyroidism), in comparison with control subjects and with patients at risk for ED, such as patients with obesity and with type II diabetes mellitus, and the role of age. Spontaneous deposition and International Index of Erectile Dysfunction (IIEF)-5 questionnaire were considered for control subjects and for all patients. Spontaneous deposition of ED occurred for three diabetic patients, never for obese patients, thyroid patients and controls, confirming the value of IIEF-5 in detecting ED. ED was more frequent in obese subjects (42%), and in patients affected by thyroid diseases (59%), than in controls (30%), although less frequent than in type II diabetes mellitus (81%). Both below and above the age of 50 years, ED score was worse in thyroid patients than in control subjects, while ED was more frequent in obese patients than in control subjects only below the age of 50 years.

Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects.

Normal subjects and patients with adult-onset diabetes received 10 gm. of aspirin in four days. On the fourth day, the fasting serum glucose and the glucose response to oral glucose were decreased in both groups. These changes were associated with increased levels of serum insulin and pancreatic glucagon, although the glucagon responses to oral glucose were unchanged. In the diabetic patients, aspirin therapy was followed by a decreased glucose response to I.V. glucose and by the appearance of an early insulin peak, which could not be demonstrated before treatment. Aspirin did not affect the I.V. glucose tolerance in normal subjects, although it did enhance the early insulin peak. A decrease in the fasting levels of free fatty acids was noted in both groups, whereas the fasting level of triglycerides decreased only in the diabetic patients. Cholesterolemia did not change in either group. A few preliminary observations indicate that, in normal subjects, ibuprofen and ketoprofen, two other presumed prostaglandin inhibitors, did not affect fasting glycemia, glucose tolerance, or the insulin response to glucose. No changes were noted after the administration of placebo.

Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts.

Because the pituitary contains hormones with beta-cell trophic activity, we evaluated whether cotransplantation of pituitary tissue with pancreatic islets might be beneficial for islet graft function and survival. Streptozotocin diabetic nude mice were transplanted under the kidney capsule with 150 handpicked islets alone or mixed with two diced pituitaries and were then followed for 4 weeks. Mice transplanted with mixed islet/pituitary grafts had higher levels of circulating prolactin (PRL) than mice transplanted with islets only, while serum cortisol, growth hormone, and follicle-stimulating hormone were similar in the two groups. After transplantation, recipients of mixed islet/pituitary grafts showed a more pronounced decrease in glycemic levels and higher systemic insulin levels than mice transplanted only with islets. Mixed islet/pituitary grafts were macroscopically characterized by an excellent vascularization and were biochemically characterized by higher insulin and PRL content than pure islet grafts. Histologically, posttransplantation remodeling originated a hybrid organ in which healthy, well-vascularized islets were adjacent to pituitary cell clusters. Transplantations performed to address the specific effect of the anterior versus the intermediate pituitary lobes indicated the former as responsible for the improved function of cotransplanted islets. Mixed islet/pituitary grafts composed of anterior lobes were also the best vascularized and were histologically characterized by the presence of many folliculo-stellate cells. In conclusion, we obtained evidence that pituitary cotransplantation significantly improves the function, insulin content, and vascularization of suboptimal islet grafts. Evidence suggesting that ectopically produced PRL and/or locally released angiogenic peptides might play a causal role is provided.

Impairment of lymphocyte-suppressive system in recent-onset insulin-dependent diabetes mellitus. Correlation with metabolic control.

Impairment of suppressor-cell activity may be important in the pathogenesis and maintenance of insulin-dependent diabetes mellitus (IDDM). In 23 recent-onset IDDM patients, lymphocyte sensitivity in vitro to theophylline was tested both in basal conditions and after improvement of metabolic control. This pharmacologic agent is mainly effective on a lymphocytic subpopulation with phenotypic and functional suppressive features. Peripheral blood lymphocytes from IDDM patients showed a loss of theophylline sensitivity, identified as inhibition of both E-rosette formation and blastogenic response to polyclonal mitogens concanavalin A (ConA) and phytohemagglutinin (PHA). An inverse relationship was demonstrated between the theophylline-induced suppression of ConA blastogenic response and blood glucose and glycosylated hemoglobin levels (P less than .01). Metabolic control seemed to be important even in relation to lymphocyte subpopulation distribution. In IDDM patients we found a significant (P less than .05) reduction of OKT4+ lymphocytes that is correlated with blood glucose and glycosylated hemoglobin levels (P less than .01). The improvement of metabolic control led to recovery of theophylline sensitivity. We suggest a deficiency in a suppressive system that could be involved in IDDM onset and the possible role of metabolic control in the impairment of some immunologic functions reported with this pathologic condition.

Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans.

The purpose of the study was to evaluate fasting endothelin-1 levels in subjects with syndrome X, in subjects with insulinoma, and in normal subjects. The single and synergistic contributions of insulin and triglyceride levels to endothelin-1 release were studied in normal subjects. This was achieved by the evaluation of endothelin-1 levels in response to an insulin bolus combined with a euglycemic clamp (protocol A) and during intralipid (test 1) or saline (test 2) infusions lasting 360 min (protocol B). In protocol B, a euglycemic two-step hyperinsulinemic (25 and 125 mU x kg-1 x h-1) clamp was started at 120 min. Subjects with syndrome X showed significantly higher endothelin-1 levels than normal subjects and subjects with insulinoma (7.22 +/- 0.89 vs. 2.61 +/- 0.38 and 2.49 +/- 0.24 pg/ml, P < 0.01). After an insulin bolus, endothelin-1 levels peaked at 10 min (3.71 +/- 0.96 pg/ml). The incremental area of endothelin-1 was significantly higher after insulin than after a saline bolus. In test 1, an acute increase in triglyceride levels significantly enhanced endothelin-1 levels, with were further increased by the synergistic contribution of high insulin and triglyceride levels. In test 2, endothelin-1 release was achieved at high insulin levels but remained significantly lower than in test 1. In conclusion, subjects with syndrome X showed higher endothelin-1 levels than normal subjects and subjects with insulinoma. These levels were reproduced in normal subjects by a simultaneous increase in insulin and triglyceride levels.

Hyperinsulinemia decreases second-phase but not first-phase arginine-induced insulin release in humans.

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU.kg-1.min-1) and a high-dose (1.20 mU.kg-1.min-1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means +/- SE) 60.0 +/- 2.4, 165.6 +/- 1.8, and 455.4 +/- 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 +/- 10.1, 73.7 +/- 12.8, and 73.4 +/- 10.3 pmol/kg, whereas second phase was 266.1 +/- 46.0, 143.1 +/- 33.5, and 133.0 +/- 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)