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Biomedical subjects

Giovanni Pacini

Publications and source records attributed to Giovanni Pacini.

At least 19 recordsLinked to original sources
PubMed2007

Improved usability of the minimal model of insulin sensitivity based on an automated approach and genetic algorithms for parameter estimation.

Minimal model analysis of glucose and insulin data from an IVGTT (intravenous glucose tolerance test) is widely used to estimate insulin sensitivity; however, the use of the model often requires intervention by a trained operator and some problems can occur in the estimation of model parameters. In the present study, a new method for minimal model analysis, termed GAMMOD, was developed based on genetic algorithms for the estimation of model parameters. Such an algorithm does not require the fixing of initial values for the parameters (that may lead to unreliable estimates). Our method also implements an automated weighting scheme not requiring manual intervention of the operator, thus improving the usability of the model. We studied a group of 170 women with a history of previous gestational diabetes. Results obtained by GAMMOD were compared with those obtained by MINMOD (a traditional gradient-based algorithm for minimal model analysis). Insulin sensitivity by GAMMOD was (3.86+/-0.19) compared with (4.33+/-0.20) x 10(-4) micro-units.ml(-1) x min(-1) by MINMOD; glucose effectiveness was 0.0236+/-0.0005 compared with 0.0229+/-0.0005 min(-1) respectively. The difference in the estimation by the two methods was within the precision expected for such metabolic parameters and is probably of no clinical relevance. Moreover, both the coefficient of variation of the estimated parameters and the error of fit were generally lower in GAMMOD, despite the fact that it does not require manual intervention. In conclusion, the GAMMOD approach for parameter estimation in the minimal model provides a reliable estimation of the model parameters and improves the usability of the model, thus facilitating its further use and application in a clinical context.

Adult↗
PubMed2006

Non-invasive glucose monitoring: assessment of technologies and devices according to quantitative criteria.

Aim of this review was to describe the main technologies for non-invasive glucose monitoring and the corresponding most relevant devices. The review tries to overcome the limitations of previous reviews on this topic, such as the lack of objective criteria for inclusion or exclusion of technologies or devices, and the poor organization of the information, which often does not allow easy comparison between technologies and devices. In this review, the information is concise and organized into specific categories, and hence it becomes easy to compare advantages and disadvantages of the different technologies and devices. For technologies, the categories of information considered are the technology name, the underlying physical principle, the technology limitations and the measurement sites on the human body. For devices, the categories of information are the device name, its approval condition (FDA Approval and/or CE Mark), the technology on which it is based, a device general description, the tests performed on the device, the corresponding results, safety information, aspects affecting usability, current status of the device and the manufacturer, an Internet reference for the device. A total of 14 technologies and 16 devices are included. Conclusions of the review were that, despite some interesting and promising technologies and devices, a satisfactory solution to the non-invasive glucose monitoring problem still requires further efforts.

Adult↗
PubMed2006

Insulin resistance as a determinant of platelet activation in obese women.

OBJECTIVES: We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. BACKGROUND: Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women. METHODS: We performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, S(I), and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured. RESULTS: Obese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B2 (11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/l), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower S(I) (median 2.51 vs. 5.0 10(4) min(-1)/[microU/ml], p < 0.002) and adiponectin (6.3 vs. 10 microg/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (beta = 0.27, p < 0.05) and S(I) (beta = -0.72, p < 0.04) predicted 11-dehydro-TXB2 excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2 in 10 women with impaired S(I) and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S(I) (+92%) and decreased CD40L (-27%), CRP (-37%), and 11-dehydro-TXB2 (-53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2 excretion (-43%, p < 0.05) without changes in body weight. CONCLUSIONS: Insulin resistance is a major determinant of platelet activation in female obesity.

Adult↗
PubMed2006

A Paleolithic diet confers higher insulin sensitivity, lower C-reactive protein and lower blood pressure than a cereal-based diet in domestic pigs.

BACKGROUND: A Paleolithic diet has been suggested to be more in concordance with human evolutionary legacy than a cereal based diet. This might explain the lower incidence among hunter-gatherers of diseases of affluence such as type 2 diabetes, obesity and cardiovascular disease. The aim of this study was to experimentally study the long-term effect of a Paleolithic diet on risk factors for these diseases in domestic pigs. We examined glucose tolerance, post-challenge insulin response, plasma C-reactive protein and blood pressure after 15 months on Paleolithic diet in comparison with a cereal based swine feed. METHODS: Upon weaning twenty-four piglets were randomly allocated either to cereal based swine feed (Cereal group) or cereal free Paleolithic diet consisting of vegetables, fruit, meat and a small amount of tubers (Paleolithic group). At 17 months of age an intravenous glucose tolerance test was performed and pancreas specimens were collected for immunohistochemistry. Group comparisons of continuous variables were made by use of the t-test. P < 0.05 was chosen for statistical significance. Simple and multivariate correlations were evaluated by use of linear regression analysis. RESULTS: At the end of the study the Paleolithic group weighed 22% less and had 43% lower subcutaneous fat thickness at mid sternum. No significant difference was seen in fasting glucose between groups. Dynamic insulin sensitivity was significantly higher (p = 0.004) and the insulin response was significantly lower in the Paleolithic group (p = 0.001). The geometric mean of C-reactive protein was 82% lower (p = 0.0007) and intra-arterial diastolic blood pressure was 13% lower in the Paleolithic group (p = 0.007). In evaluations of multivariate correlations, diet emerged as the strongest explanatory variable for the variations in dynamic insulin sensitivity, insulin response, C-reactive protein and diastolic blood pressure when compared to other relevant variables such as weight and subcutaneous fat thickness at mid sternum. There was no obvious immunohistochemical difference in pancreatic islets between the groups, but leukocytes were clearly more frequent in sampled pancreas from the Cereal group. CONCLUSION: This study in domestic pigs suggests that a Paleolithic diet conferred higher insulin sensitivity, lower C-reactive protein and lower blood pressure when compared to a cereal based diet.

Journal Article↗
PubMed2006

The role of endocrine counterregulation for estimating insulin sensitivity from intravenous glucose tolerance tests.

CONTEXT: During insulin-modified frequently sampled iv glucose tolerance tests (IM-FSIGT), which allow assessment of insulin action, plasma glucose can markedly decrease. OBJECTIVE: This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model-derived indices of insulin sensitivity (S(I)) and glucose effectiveness. PARTICIPANTS: Thirteen nondiabetic volunteers (seven males, six females, aged 26 +/- 1 yr, body mass index 22.1 +/- 0.7 kg/m(2)) were studied. DESIGN: All participants were studied in random order during IM-FSIGT (0.3 g/kg glucose; 0.03 U/kg insulin at 20 min) and during identical conditions but with a variable glucose infusion preventing a decrease of plasma glucose concentration below euglycemia (IM-FSIGT-CLAMP). Five participants additionally underwent euglycemic-hyperinsulinemic (1 mU.kg(-1).min(-1)) clamp tests. RESULTS: Plasma glucose declined during IM-FSIGT to its nadir of 50 +/- 3 mg/dl at 60 min in parallel to a rise (P < 0.05 vs. basal) of plasma glucagon, cortisol, epinephrine, and GH. Glucose infusion rates of 4.6 +/- 0.5 mg.kg(-1).min(-1) between 30 and 180 min during IM-FSIGT-CLAMP prevented the decline of plasma glucose and the hypoglycemia counterregulatory hormone response. S(I) was approximately 68% lower during IM-FSIGT (3.40 +/- 0.36 vs. IM-FSIGT-CLAMP: 10.71 +/- 1.06 10(-4).min(-1) per microU/ml, P < 0.0001), whereas glucose effectiveness did not differ between both protocols (0.024 +/- 0.002 vs. 0.021 +/- 0.003 min(-1), P = NS). Compared with the euglycemic hyperinsulinemic clamp test, S(I) expressed in identical units from IM-FSIGT was approximately 66% (P < 0.001) lower but did not differ between the euglycemic hyperinsulinemic clamp test and the IM-FSIGT-CLAMP (P = NS). CONCLUSIONS: The transient fall of plasma glucose during IM-FSIGT results in lower estimates of S(I), which can be explained by hormonal response to hypoglycemia.

Adult↗
PubMed2006

The hyperbolic equilibrium between insulin sensitivity and secretion.

AIM: The interrelationship between insulin resistance and beta cell secretion has been qualitatively described by a hyperbolic function and quantitatively by the disposition index. The concepts behind these assumptions are however still controversial and this review aims to briefly recall the main aspects of the hyperbolic paradigm in terms of mathematical representation and derived indices, together with the main criticisms of the various features. SYNTHESIS: The relationship is analyzed in terms of a qualitative curve with respect to a possible physiological mechanism underlying that particular shape. Quantitatively, the disposition index, which derives from the non-linear hyperbola-like curve, provides an integrated figure of glucose tolerance including both insulin sensitivity and secretion. Different types of metabolic tests and different categories of subjects may yield different mathematical relationships between the two processes. However, various formulas for the disposition index can be wrong and the reasons for this are highlighted. CONCLUSIONS: Insulin secretion and insulin sensitivity are related with an inverse, non-linear function that shows the critical importance of the beta cell dysfunction for the development of type 2 diabetes. The disposition index is a mirror of glucose tolerance and may be important for evaluating those factors that (hypothetically) signal to the beta cell the reduction of insulin sensitivity, for development of possible novel treatments that restore the normal relation between the insulin resistance and the pancreatic activity.

Blood Glucose↗
PubMed2006

Preeclampsia in lean normotensive normotolerant pregnant women can be predicted by simple insulin sensitivity indexes.

Certain similarities between preeclampsia and insulin resistance syndrome suggest a possible link between the 2 diseases. The aim of our study was to evaluate 3 insulin sensitivity (IS) indexes (fasting homeostasis model assessment IS [ISHOMA], quantitative insulin sensitivity check index [ISQUICKI], and oral glucose IS [OGIS]) early and late in pregnancy in a large number of normotensive pregnant women with a normal glucose tolerance and to test the ability of these indexes to predict the risk of subsequent preeclampsia. In all, 829 pregnant women were tested with a 75-g, 2-hour oral glucose load in 2 periods of pregnancy: early (16 to 20 weeks) and late (26 to 30 weeks). In early and late pregnancy, respectively, IS(HOMA) was 1.23+/-0.05 and 1.44+/-0.05 (P<0.01), IS(QUICKI) was 0.40+/-0.002 and 0.38+/-0.002 (P<0.01), and OGIS was 457+/-2.4 mL min(-1) m(-2) and 445+/-2.2 (P<0.001), all confirming the reduction in insulin sensitivity during pregnancy. Preeclampsia developed in 6.4% of the pregnant women and correlated positively with the 75th centile of IS(HOMA) (P=0.001), with a sensitivity of 79% in the early and 83% in the late period and a specificity of 97% in both. IS(QUICKI) <25th centile was also related with preeclampsia (P=0.001), with a sensitivity of 85% in the early and 88% in the late period and a specificity of 97% in both. Judging from our findings, ISHOMA and ISQUICKI are simple tests that can pinpoint impaired insulin sensitivity early in the pregnancy. Given their high sensitivity and specificity, these indexes could be useful in predicting the development of preeclampsia in early pregnancy, before the disease become clinically evident.

Adult↗
PubMed2006

Increased plasma amylin in type 1 diabetic patients after kidney and pancreas transplantation: A sign of impaired beta-cell function?

OBJECTIVE: In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones. RESEARCH DESIGN AND METHODS: Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS: PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P < 0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P < 0.004). CONCLUSIONS: After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT.

Adult↗
PubMed2005

Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT.

A frequently used index of beta-cell function from the OGTT is the insulinogenic index, IGI. However, there is still some controversy about its validity. In a group of 145 women with different degrees of glucose tolerance, we compared IGI to the corresponding index with C-peptide, DeltaCP(30)/DeltaG(30), which better describes beta-cell function. We also validated both indices with measurements of beta-cell function derived from IVGTT. IGI strongly correlated (R = 0.82, P < 0.0001) with DeltaCP(30)/DeltaG(30). Both IGI and DeltaCP(30)/DeltaG(30) correlated significantly with the corresponding index from IVGTT, though IGI correlation was stronger (IGI: R = 0.67, P < 0.0001; DeltaCP(30)/DeltaG(30): R = 0.56, P < 0.0001). Also indices derived from areas under the curve of insulin, glucose and C-peptide were analyzed. Finally, we compared IGI to similar indices with samples at 60, 90 and 120 min, more often available than that at 30 min. We conclude that IGI is an acceptable index of beta-cell function, as also mirrored by DeltaCP(30)/DeltaG(30). However, the weaker correlation of the C-peptide index with the more accurate index from the IVGTT suggests that it should be used with caution. The index at 60 min can be used as surrogate of IGI, but not the indices at 90 and 120 min.

Area Under Curve↗
PubMed2005

Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice.

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.

Administration, Oral↗
PubMed2005

Subdiaphragmatic vagal deafferentation affects body weight gain and glucose metabolism in obese male Zucker (fa/fa) rats.

We investigated the effect of subdiaphragmatic vagal deafferentation (SDA) on food intake, body weight gain, and metabolism in obese (fa/fa) and lean (Fa/?) Zucker rats. Before and after recovery from surgery, food intake and body weight gain were recorded, and plasma glucose and insulin were measured in tail-prick blood samples. After implantation of a jugular vein catheter, an intravenous glucose tolerance test (IVGTT) was performed, followed by minimal modeling to estimate the insulin sensitivity index. Food intake relative to metabolic body weight (g/kg(0.75)) and daily body weight gain after surgery were lower (P < 0.05) in SDA than in sham obese but not lean rats. Before surgery, plasma glucose and insulin concentrations were lower (P < 0.05) in lean than in obese rats but did not differ between surgical groups within both genotypes. Four weeks after surgery, plasma glucose and insulin were still similar in SDA and sham lean rats but lower (P < 0.05) in SDA than in sham obese rats. IVGTT revealed a downward shift of the plasma insulin profile by SDA in obese but not lean rats, whereas the plasma glucose profile was unaffected. SDA decreased (P < 0.05) area under the curve for insulin but not glucose in obese rats. The insulin sensitivity index was higher in lean than in obese rats but was not affected by SDA in both genotypes. These results suggest that elimination of vagal afferent signals from the upper gut reduces food intake and body weight gain without affecting the insulin sensitivity index measured by minimal modeling in obese Zucker rats.

Animals↗
PubMed2005

Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease.

Circulating levels of four adipokines (adiponectin, TNF-alpha, leptin, and resistin) and the postprandial lipid and adiponectin responses to an oral fat load were assessed in 25 non-obese, non-diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH) and correlated with metabolic indices and liver histology. Circulating adiponectin was lower in NASH compared with controls (5,476 +/- 344 vs. 11,548 +/- 836 ng/mL; P = .00001) and on multiple regression analysis correlated negatively with liver steatosis, necroinflammation (OR = 5.0; P = .009), and fibrosis (OR = 8.0; P = .003). The magnitude of postprandial lipemia was significantly higher in NASH than in controls and was related to fasting adiponectin (beta = -0.78; P = .00003). Controls showed a significant increase in serum adiponectin in response to the fat load, whereas patients with NASH showed a slight decrease. Postprandial free fatty acids response correlated inversely with adiponectin response in both groups and independently predicted the severity of liver steatosis in NASH (beta = 0.51; P = .031). In conclusion, hypoadiponectinemia is present before overt diabetes and obesity appear and correlates with the severity of liver histology in NASH. Impaired postprandial lipid metabolism may be an additional mechanism linking hypoadiponectinemia and NASH and posing a higher cardiovascular risk to these subjects. The mechanism(s) underlying these differences are unknown, but the type of dietary fat seems to play a role. These findings may have important pathogenetic and therapeutic implications in both liver and metabolic disease.

Adiponectin↗
PubMed2005

The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus.

OBJECTIVE: To compare the effects of a 4-month strength training (ST) versus aerobic endurance training (ET) program on metabolic control, muscle strength, and cardiovascular endurance in subjects with type 2 diabetes mellitus (T2D). DESIGN: Randomized controlled trial. SETTING: Large public tertiary hospital. PARTICIPANTS: Twenty-two T2D participants (11 men, 11 women; mean age +/- standard error, 56.2+/-1.1 y; diabetes duration, 8.8+/-3.5 y) were randomized into a 4-month ST program and 17 T2D participants (9 men, 8 women; mean age, 57.9+/-1.4 y; diabetes duration, 9.2+/-1.7 y) into a 4-month ET program. INTERVENTIONS: ST (up to 6 sets per muscle group per week) and ET (with an intensity of maximal oxygen consumption of 60% and a volume beginning at 15 min and advancing to a maximum of 30 min 3x/wk) for 4 months. MAIN OUTCOME MEASURES: Laboratory tests included determinations of blood glucose, glycosylated hemoglobin (Hb A1c), insulin, and lipid assays. RESULTS: A significant decline in Hb A1c was only observed in the ST group (8.3%+/-1.7% to 7.1%+/-0.2%, P=.001). Blood glucose (204+/-16 mg/dL to 147+/-8 mg/dL, P<.001) and insulin resistance (9.11+/-1.51 to 7.15+/-1.15, P=.04) improved significantly in the ST group, whereas no significant changes were observed in the ET group. Baseline levels of total cholesterol (207+/-8 mg/dL to 184+/-7 mg/dL, P<.001), low-density lipoprotein cholesterol (120+/-8 mg/dL to 106+/-8 mg/dL, P=.001), and triglyceride levels (229+/-25 mg/dL to 150+/-15 mg/dL, P=.001) were significantly reduced and high-density lipoprotein cholesterol (43+/-3 mg/dL to 48+/-2 mg/dL, P=.004) was significantly increased in the ST group; in contrast, no such changes were seen in the ET group. CONCLUSIONS: ST was more effective than ET in improving glycemic control. With the added advantage of an improved lipid profile, we conclude that ST may play an important role in the treatment of T2D.

Aged↗
PubMed2005

Assessment of insulin secretion in relation to insulin resistance.

PURPOSE OF REVIEW: In healthy individuals, upregulation of insulin secretion compensates for insulin resistance so that normal glucose tolerance is maintained. Thus insulin secretion should be evaluated in relation to insulin sensitivity, as failure to account for insulin resistance may prevent the detection of beta-cell defects. Numerous studies have considered this problem, but how insulin secretion is regulated by insulin sensitivity and how insulin secretion should be quantitatively expressed to account for sensitivity are issues still under debate. This review will discuss these concepts and the aspects that should be considered for an appropriate solution to the problem. RECENT FINDINGS: While the historical paradigm of a specific hyperbolic relationship between some particular insulin secretion and insulin sensitivity indices has recently been confirmed, it has been suggested that this paradigm is not applicable to all the indices. It has also been suggested that for some relevant insulin secretion indices this relationship may not exist. Thus, the classical insulin secretion index that accounts for sensitivity, the so-called disposition index, should be used cautiously, as it presupposes a hyperbolic relationship. Furthermore, it has been pointed out that the assessment of this relationship requires independency of the indices. SUMMARY: The assessment of insulin secretion in relation to insulin sensitivity is important in the study of glycemic control but requires appropriate methods and cautious interpretations. Blind application of principles that are valid for specific insulin secretion and sensitivity indices may produce false results.

Blood Glucose↗
PubMed2005

Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis.

OBJECTIVES: The relationships between the adipokines tumor necrosis factor (TNF)-alpha and adiponectin and the parameters of glucose homeostasis and severity of liver disease were assessed in nonobese nondiabetic subjects with nonalcoholic steatohepatitis (NASH). METHODS: A frequently sampled intravenous glucose tolerance test, serum cytokine measurement, and 7-day alimentary record were performed in 20 biopsy-proven NASH patients and 45 age-, sex-, and BMI-matched controls (30 insulin sensitive and 15 insulin resistant). RESULTS: Patients with NASH had impaired pancreatic beta-cell function compared with both insulin-sensitive (adaptation index, AI: 97.7 +/- 17.7 vs 307.4 +/- 24.1 min(-2) mmol(-1) L; p= 0.00001) and insulin-resistant (adaptation index, AI: 97.7 +/- 17.7 vs 201.4 +/- 41.1 min(-2) mmol(-1) L; p= 0.001) controls. Serum adiponectin levels were also significantly lower in the NASH group than in the two control groups and correlated with adaptation index and with the severity of hepatic steatosis, necroinflammation, and fibrosis. When NASH patients were grouped according to the severity of histological liver damage, adiponectin was the only variable discriminating patients with higher necroinflammatory grade and fibrosis score from those with milder lesions. CONCLUSIONS: Beta-cell secretory impairment is present in nonobese patients with NASH before glucose intolerance appears and may contribute to their increased risk for developing diabetes. Hypoadiponectinemia is a feature of NASH and may have a pathogenetic role in beta-cell dysfunction and in hepatic necroinflammation and fibrosis, independently of insulin resistance, visceral fat accumulation, TNF-alpha axis activity, and dietary habits. Our findings provide further rationale for therapeutic approaches aimed at increasing adiponectin levels together with restoring beta-cell function and insulin sensitivity.

Adaptation, Physiological↗
PubMed2005

Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.

OBJECTIVE: To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related beta-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS: In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA(1c) (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference -1.0 +/- 0.2%; P < 0.001; baseline of all subjects combined 7.7 +/- 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference -0.9 +/- 0.3 mmol/l, P = 0.016; baseline 9.8 +/- 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 +/- 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 +/- 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 +/- 4 ml x min(-1) x m(-2), P = 0.036; baseline 246 +/- 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 +/- 1.0, P = 0.040; baseline 9.1 +/- 0.5). The change in adaptation index correlated to the change in A1C (r = -0.39, P = 0.004). CONCLUSIONS: This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves beta-cell function along with improved postmeal insulin sensitivity.

Adamantane↗