Biomedical subjects

G Pacini

Publications and source records attributed to G Pacini.

At least 55 records · Page 3Linked to original sources

PubMed1998

Distribution and kinetics of amylin in humans.

The aim of the study was to determine the apparent volume of distribution (VTOT), total body clearance (CL), fractional clearance, and mean residence time (MRT) of the beta-cell hormone amylin. We therefore performed an intravenous injection of 50 micrograms of human synthetic amylin (amlintide) in nine healthy male subjects during suppression of endogenous amylin release by intravenous somatostatin (0.06 microgram.kg-1.min-1). The plasma levels of amylin concentrations over time were analyzed using three-exponential curves. VTOT was 173 +/- 16 ml/kg and was not different from that of insulin reported in the literature (157 ml/kg). MRT was 27.7 +/- 2.1 min and thus two times the reported value for insulin (14.1 min) and C-peptide (16.4 min). CL and fractional CL were 6.2 +/- 0.2 ml.kg-1.min-1 and 0.038 +/- 0.003 min-1, respectively. Fractional CL is therefore definitely lower than that reported for insulin (0.12-0.2 min-1) but is, however, in the range of that of C-peptide (0.05 min-1). In conclusion, clearance of amylin is similar to that reported for C-peptide and much slower than insulin, indicating that the commonly used molar insulin-to-amylin ratio does not reflect the correct relationship of the two peptides.

Adult↗

PubMed1998

Age-related reduction in glucose elimination is accompanied by reduced glucose effectiveness and increased hepatic insulin extraction in man.

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness (SG), and hepatic extraction (HE) of insulin are altered by age when glucose tolerance is normal. A frequently sampled i.v. glucose tolerance test was performed in 20 elderly (E, 10/10 male/female, all 63 yr old) and in 20 young subjects (Y, 10/10 male/female, all 27 yr old), who were similar in body mass index and 2-h blood glucose during oral glucose tolerance test. E exhibited impaired glucose elimination (i.v. tolerance index, 1.31 +/- 0.10 vs. 1.70 +/- 0.12% min-1; P = 0.019). First-phase insulin secretion and SI did not differ between the groups, whereas E had lower glucose sensitivity of second-phase insulin secretion (0.40 +/- 0.07 vs. 0.70 +/- 0.08 (pmol/L)min-2/(mmol/L), P = 0.026), lower SG, 0.017 +/- 0.002 vs. 0.025 +/- 0.002 min-1, P = 0.004), and higher HE (81.3 +/- 2.4 vs. 73.2 +/- 2.1%, P = 0.013). Across both groups, SG correlated positively with glucose tolerance index (r = 0.58, P < 0.001) and negatively with HE (r = -0.54, P < 0.001). Plasma leptin and glucagon did not change by age, whereas plasma pancreatic polypeptide (PP) was higher in E (122 +/- 18 vs. 66 +/- 6 pg/mL, P = 0.004). PP did not, however, correlate to any other parameter. We conclude that E subjects with normal oral glucose tolerance have reduced SG, impaired second-phase insulin secretion, and increased HE, whereas SI and first-phase insulin secretion seem normal. SG seems most related to age-dependent impairment of glucose elimination, whereas leptin, glucagon, and PP do not seem to contribute.

Adult↗

PubMed1997

Amylin: history and overview.

The presence of amyloid deposits in the pancreas was first described at the beginning of the 20th century. However, it was not until 1987 that the structure of the amylin molecule was identified. Amylin is a 37-amino-acid peptide hormone that is co-secreted with insulin by the pancreatic beta-cells in response to a nutrient stimulus. It is deficient in patients with Type 1 diabetes and elevated in patients in the early stages of Type 2 diabetes, a condition which is characterized by hyperinsulinaemia. Elevation of plasma amylin levels has also been described in patients with impaired glucose tolerance, obese subjects and in pregnant women with both normal glucose tolerance and gestational diabetes mellitus. However, it appears that deficiencies of amylin secretion appear before those of insulin in patients in the later stages of Type 2 diabetes. Early experimental studies suggested that amylin inhibits basal insulin secretion, and induces insulin resistance in skeletal muscle, leading to the hypothesis that it has a role in the aetiology of Type 2 diabetes. However, a number of more recent experimental studies have indicated that amylin is a third active pancreatic islet hormone that works with insulin and glucagon to maintain glucose homeostasis. Amylin appears to regulate glucose inflow to the circulation by influencing the rate of gastric emptying, and thus the rate at which meal-derived glucose enters the system, and also by inhibiting glucose release and hepatic glucose production in the postprandial period.

Amyloid↗

PubMed1997

Amylin release during oral glucose tolerance test.

The role of amylin in the beta-cell dysfunction that occurs in patients with diabetes mellitus may be important. Amyloid deposits are found in the pancreata of subjects with Type 2 diabetes and may contribute to beta-cell death. It is therefore necessary to study amylin secretion and kinetics to determine whether elevated levels of the peptide are due to elevated secretion, reduced clearance or both. The aim of this study was to measure amylin dynamics during an oral glucose tolerance test (OGTT). We also used a mathematical model of beta-cell activity to assess the secretion and kinetics of C-peptide, insulin and amylin in humans during an OGTT. In particular, we were interested in characterizing the physiological meaning of one of the terms in the model, the amylin/C-peptide co-secretion factor (sigma). The model has been used in several pathophysiological conditions and results indicate an elevated secretion and clearance of amylin in glucose-intolerant states. Amylin clearance has been found to be similar to that of C-peptide, and much slower than that of insulin. In this study, direct measurements of insulin and amylin secretion in five obese subjects yielded an estimate of the amylin/insulin co-secretion factor of 0.004 with a standard deviation (SD) of 0.002. The point estimate of hepatic clearance was 80 ml min(-1), which was much lower than that of insulin (507 +/- 94 ml min[-1]). In addition, the estimated hepatic clearance was not significantly different from zero given its high SD of 213 ml min(-1). The absence of hepatic extraction of amylin is therefore a plausible hypothesis, which is also supported by the similarity between amylin and C-peptide clearances. This observation characterizes the physiological meaning of sigma and suggests that this parameter is associated mainly with beta-cell secretion.

Amyloid↗

PubMed1997

Impaired adaptation of first-phase insulin secretion in postmenopausal women with glucose intolerance.

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness, and hepatic extraction of insulin are altered in subjects with impaired glucose tolerance (IGT). The frequently sampled intravenous glucose tolerance test was performed in postmenopausal women (age 63 yr, body mass index range 21.6-28.9 kg/m2) with IGT (n = 10) or normal glucose tolerance (NGT; n = 10). Insulin sensitivity (S(I)) was significantly lower in IGT than in NGT (P = 0.030). In contrast, insulin secretion was not significantly different between the two groups as determined by area under the curve for insulin and C-peptide, acute insulin response to glucose (AIR(G)), and glucose sensitivity of first-phase (phi1) or of second-phase (phi2) insulin secretion. In NGT (r = -0.68, P = 0.029) but not in IGT (r = -0.05, not significant), S(I) correlated negatively with phi1. The B-cell "adaptation index" (S(I) x phi1) was lower in IGT than in NGT [83 +/- 25 vs. 171 +/- 29 min(-2)/(mmol/l), P = 0.042]. Also, the B-cell "disposition index" (S(I) times AIR(G)) was lower in IGT (83 +/- 25 10(-4) min(-1)) than in NGT (196 +/- 30 10(-4) min(-1), p = 0.011). In contrast, glucose effectiveness or hepatic extraction of insulin was not different between IGT and NGT. We conclude that postmenopausal women with IGT fail to adequately adapt to lowered S(I) by increasing first-phase insulin secretion.

Analysis of Variance↗

PubMed1997

Elevated islet amyloid pancreatic polypeptide and proinsulin in lean gestational diabetes.

Recent research indicates that islet amyloid pancreatic polypeptide (IAPP) might have a regulatory effect on beta-cell insulin processing and secretion. To study such interaction in more detail, IAPP secretion and kinetics and the serum concentrations of proinsulin were assessed both before and after delivery in lean pregnant women with gestational diabetes mellitus (GDM patients) in comparison to those with normal glucose tolerance (NGT) and to nonpregnant healthy lean (control) and obese insulin-resistant women during oral glucose tolerance tests. Kinetic analysis of IAPP was performed with mathematical modeling, providing indirect estimates of its secretion and fractional clearance. Total insulin secretion per 180 min was elevated by 30% in GDM patients (35 +/- 3 pmol/l) versus control subjects (27 +/- 1 pmol/l) (P < 0.05), but increased even more (190-250%) in obese insulin-resistant women, compared with all other groups (68 +/- 7 pmol/l, P < 0.0005). Pregnancy induced a more marked fourfold increase in apparent total IAPP secretion rate (TIR) (GDM patients, 172 +/- 31 pmol x 1(-1) x 3 h(-1); NGT subjects, 166 +/- 31 pmol x 1(-1) x 3 h(-1); control subjects, 40 +/- 1 pmol 1(-1) x 3 h(-1)) and a twofold rise in its fractional clearance versus control subjects (P < 0.01), whereas in GDM patients a 30% increase of IAPP secretion and a decreased clearance was found, compared with obese insulin-resistant women (TIR, 112 +/- 14 pmol x 1(-1) x 3 h(-1)). The increase in IAPP secretion in both pregnant groups was much higher than that of the insulin groups, resulting in a marked change of the IAPP-insulin cosecretion factor when compared with lean or obese nonpregnant women (P < 0.0005). Associated serum proinsulin and the postprandial (total divided by 180 min) proinsulin-to-insulin ratio were greater in GDM patients versus NGT and control subjects (0.11 +/- 0.01 vs. 0.07 +/- 0.01 and 0.08 +/- 0.01 pmol/l, P < 0.05), while the fasting proinsulin-to-insulin ratio was only increased in GDM patients versus control subjects (0.22 +/- 0.03 vs. 0.13 +/- 0.01 pmol/l, P < 0.05). After delivery, total IAPP secretion (52.4 +/- 1.5 pmol/l) was completely normalized in the GDM group, as were the clearance rate and the IAPP-insulin cosecretion factor. Similarly, serum proinsulin concentrations returned to normal, whereas proinsulin-to-insulin ratios remained elevated. In conclusion, IAPP hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion. Increased proinsulin concentrations and a raised proinsulin-to-insulin ratio, which did not abate following delivery, are specific to GDM and might thus serve as its marker and potentially even identify subjects at high risk for the development of NIDDM.

Adult↗

PubMed1997

Pronounced insulin resistance and inadequate beta-cell secretion characterize lean gestational diabetes during and after pregnancy.

OBJECTIVE: To evaluate beta-cell secretion and glucose metabolism in lean subjects with gestational diabetes mellitus (GDM) compared with that in subjects with normal pregnancy and obesity. RESEARCH DESIGN AND METHODS: Insulin secretion, insulin sensitivity (S1), and hepatic insulin extraction were assessed in pregnant women with GDM before and after delivery and in those with normal glucose tolerance (NGT) in comparison to healthy nonpregnant lean and obese women. Kinetic analysis of glucose, insulin, and C-peptide plasma concentrations during oral and intravenous glucose tolerance tests was performed by mathematical modeling. RESULTS: S1 was blunted in pregnant women with GDM by 84% and in those with NGT by 66% compared with lean nonpregnant women (P < 0.005 vs. healthy nonpregnant lean control subjects; P < 0.05, GDM vs. pregnant women with NGT), whereas glucose effectiveness was decreased by 33% in both pregnant groups (P < 0.05 vs. healthy nonpregnant lean control subjects). Insulin secretion was 30% higher (P < 0.05) in subjects with GDM than in pregnant women with NGT or in nonpregnant lean women, but decreased (P < 0.005) when compared with obese women with a comparable degree of insulin resistance. Fractional hepatic insulin extraction was similar in both pregnant groups, being lower (P < 0.0001) by 30% versus nonpregnant females. beta-cell sensitivity to glucose for insulin release was decreased in subjects with GDM versus pregnant women with NGT as well as nonpregnant women by 40-50% (P < 0.01). Twelve weeks after delivery, GDM returned to normal glucose tolerance, but S1 remained 50% lower than that in lean nonpregnant women, while beta-cell sensitivity to glucose did not change (P < 0.01 vs. healthy nonpregnant lean control subjects). CONCLUSIONS: Pregnancy is characterized by insulin resistance, diminished hepatic insulin extraction, and glucose effectiveness. Lean subjects with GDM are additionally characterized by having more pronounced insulin resistance and inadequate insulin secretion, which persist after delivery. Compared with other insulin-resistant prediabetic states like impaired glucose tolerance (IGT), defective insulin secretion seems to be a predominant defect in lean GDM subjects, indicating that it might represent a specific prediabetic condition.

Adult↗

PubMed1996

Beta-cell activity and hepatic insulin extraction following dexamethasone administration in healthy subjects.

Glucocorticoids induce an increase of hepatic glucose production and peripheral resistance to insulin action. It is further assumed that dexamethasone administration in humans causes insulin hypersecretion, although inferences on beta-cell activity have been made in absolute terms and mostly from observations of systemic insulin concentration. In fact, the role of hepatic insulin extraction in humans treated long-term with glucocorticoids has not been investigated. The aim of the present study was to factor out quantitatively the main components of the insulin pathway that are responsible for the peripheral hypersecretion observed after steroids. Frequently sampled intravenous (FSIGT) and oral (OGTT) glucose tolerance tests were performed in healthy subjects before and after 5 days of oral dexamethasone administration (4 mg/d). Insulin sensitivity, beta-cell secretion, and hepatic insulin extraction were estimated by means of mathematical modeling. After steroids, insulin sensitivity decreased from 6.00 +/- 1.29 to 4.23 +/- 1.04 min-1/(microU/mL) (P < .04). Basal beta-cell secretion increased from 45 +/- 7 to 104 +/- 26 pmol/L . min-1 (P < .004) during the FSIGT and from 40 +/- 6 to 88 +/- 21 (P < .05) during the OGTT; total insulin release increased from 19 +/- 5 to 36 +/- 7 nmol/L in 180 minutes (P < .005) and from 33 +/- 5 to 50 +/- 10 (P < .02), respectively, FSIGT data also showed that first-phase beta-cell sensitivity increased from 236 +/- 39 to 309 +/- 33 pmol/L . min-1/(mg/dL) (P < .04), and second-phase from 631 +/- 154 to 1,103 +/ 196 10(4) pmol/L . min-2/(mg/dL) (P < .03). Posthepatic insulin delivery increased only insignificantly during the FSIGT (from 3.4 +/- 0.6 to 4.5 +/- 0.5 nmol/L, P = .073) due to an augmented hepatic insulin extraction from 73.0% +/- 7.2% to 83.0% +/- 3.5% (P < .05). During the OGTT, posthepatic insulin delivery increased after treatment from 6.6 +/- 1.2 to 11.4 +/- 2.5 nmol/L (P < .035) due to an increase, although slight, of hepatic insulin extraction from 77.4% +/- 1.9% to 79.3% +/- 3.3% (P = .319). The increased overall beta-cell activity during both tests was observed also by analyzing OGTT profiles of islet amyloid polypeptide (IAPP), the secretion of which was higher after steroids (basal, 0.081 +/- 0.012 v 0.272 +/- 0.082 pmol/L/min, P < .02; total, 35 +/- 8 v 116 +/- 48 mpmol/L in 3 hours, P < .05). In conclusion, after dexamethasone administration, peripheral hyperinsulinemia due to marked prehepatic beta-cell insulin hypersecretion is partially ameliorated by a concomitant increase of hepatic insulin clearance, which is more evident during a FSIGT. Model-derived secretion parameters from the OGTT and FSIGT produced comparable results, indicating that both tests, when properly analyzed, are feasible tools to evaluate insulin secretion.

Administration, Oral↗

PubMed1996

Integrated mathematical model to assess beta-cell activity during the oral glucose test.

A model describing beta-cell secretion during an oral glucose tolerance test (OGTT) is introduced. The aim was to quantify beta-cell activity in different pathologies by analyzing peripheral concentration data of insulin, C-peptide, and islet amyloid polypeptide (IAPP). Insulin appearance in periphery is given by the fraction of C-peptide secretion, CPS(t), which accounts for liver degradation. A novelty of this study is the inclusion of IAPP delivery assumed proportional to CPS(t). Although IAPP fractional clearance is estimated in every subject, the clearances of insulin and C-peptide are assigned from a wide set of previous independent studies. Sensitivity analysis was performed to quantify the "error" in the estimated variables due to these assignments. All parameters relating to beta-cell secretion increased in the glucose-intolerant states [integrated CPS(t)=56 +/- 8 nmol/l in 180 min vs. 32 +/- 3 of controls, P<0.05; total IAPP delivery= 83 +/- 21 pmol/l in 180 min vs. 41 +/- 6, P<0.05]. Elevated plasma IAPP concentration of the patients was due to augmented secretion since IAPP clearance was found to be even slightly greater than in controls, (0.053 +/- 0.011 vs. 0.034 +/- 0.004 min-1) and markedly lower than that of insulin (0.14 +/- 0.02, P<0.01). In conclusion, the model introduced here allows the characterization of beta-cell secretory parameters during a simple test such as OGTT.

Amyloid↗

PubMed1996

Plasma clearance rate of 51Cr-EDTA provides a precise and convenient technique for measurement of glomerular filtration rate in diabetic humans.

It has not yet been fully clarified whether the plasma or renal clearance approach is the most reliable to investigate GFR in humans. The study presented here aimed to compare plasma decay with renal clearance of 51Cr-EDTA in 27 diabetic patients with patterns of renal function broadly dispersed in a wide range of values. Moreover, the comparison was also performed with renal clearance of nonlabeled iothalamate in a subgroup of 17 patients. A biexponential function was found to fulfill statistical and heuristic criteria for the modeling analysis of plasma 51Cr-EDTA decay with 19 samples after bolus intravenous 51Cr-EDTA injection. Individual GFR values from 51Cr-EDTA plasma clearance highly correlated with those from renal clearance (r2 = 0.977, P < 0.0001), but resulted on average about 2.5 mL.min-1.1.73 m-2 higher (66.8 +/- 6.5 mL.min-1.1.73 m-2 (mean +/- SE) versus 64.3 +/- 6.4, P < 0.02). This difference remained relatively constant from patients with normal renal function to those with impaired renal function, suggesting that the plasma clearance is slightly less accurate than renal clearance approach because of a constant extrarenal clearance rate. In the subgroup studied, a similar difference was found between GFR values from 51Cr-EDTA plasma clearance (84.7 +/- 7.3) and renal clearance of iothalamate (82.8 +/- 7.3), although not statistically significant (P = 0.4). Individual GFR values well correlated (r2 = 0.913, P < 0.0001). The precision and reproducibility of the experimental approaches were assessed by comparing three coefficients of variation: (1) CVb of the bolus injection, because of measurement errors; (2) CVc of the continuous infusion, which additionally includes errors of urine volume measurement and physiological variability in the same day; and (3) CVr of repeated measurements by using bolus injection, which also accounts for physiological variability in different days. CVc of iothalamate and 51Cr-EDTA infusions were 7.5 +/- 1.9% and 7.4 +/- 1.2% respectively. CVb and CVr of bolus injection of 51Cr-EDTA were 2.6 +/- 0.3% and 3.5 +/- 0.8% respectively. CVb and CVr of bolus injection of 51Cr-EDTA, but not CVc of iothalamate and 51Cr-EDTA infusions were twofold to tenfold lower than the percent yearly change reported in IDDM and NIDDM patients. More particularly, CVr was significantly less than CVc. In order to make the test less cumbersome, a reduced sampling schedule with seven samples was designed and validated. GFR measured with seven samples was 66.1 +/- 6.4 (P = 0.1 when compared with the full 19-sample schedule) with a CVb of 3.5 +/- 0.5%. This seven-sample protocol was not different from that obtained with the previously described simplified method of Brøchner-Mortensen (63.9 +/- 6.8, P = 0.16), yet yielding a statistically more accurate estimate (coefficient of variation for Brøchner-Mortensen method = 12.1 +/- 2.9, P = 0.004). Moreover, only bolus injection, along with modeling analysis of plasma clearance rate, allows the accurate measurement of the extracellular fluid volume, an important parameter in diabetic patients. It was concluded that the reduced seven-plasma sample protocol is able to detect as small as 4 to 5% changes per year in a single patient. Moreover, it provides precise and accurate estimate of GFR in diabetic patients with hyperfiltration, who are postulated to be at higher risk to develop renal damage.

Chromium Radioisotopes↗

PubMed1996

On-line urea kinetics in haemodiafiltration.

BACKGROUND: Calculation of Kt/V and assessment of nutrition have so far been dependent upon off-line urea measurements of blood or dialysate samples. Here we describe a biosensor for on-line urea measurement during haemodiafiltration. Methods. The biosensor consisted of a cartridge containing covalently linked urease placed between two conductivity cells. The biosensor was placed on the outlet line of a haemofilter in series with a dialyser in order to obtain an aliquot of plasma ultrafiltrate for on-line measurement of urea. RESULTS: Urea nitrogen concentrations were highly correlated to the difference (Delta) in conductivity measured by the two conductivity cells both in aqueous solutions (in-vitro studies, y=-6. 676+32.12x, R2=0.998, P<0.0001) and in ultrafiltrates (ex-vivo studies, y=-637+32.01x, R2=0.98, P<0.00001). Delta conductivity was highly reproducible (% variation: ).8-5.3%) and stable (maximal % variation at 150 mg/dl after 100 min. 0.9+/-0.3 vs initial values). The intradialytic plasma water urea profile was obtained in 10 haemodialysis patients. To study recirculation, the plasma water urea profile was analysed before and 3 min after stopping the dialysate flow. The pre- and post-stopped flow ratio (1.21+/-0.1, mean+/-1 SD) was superimposable to conventional blood sampling data (opposite arm venous arterial: 1.22+/-0.11) and allowed correction for recirculation. A novel approach to urea kinetic modelling was described and used to reliably project end-dialysis and post-dialysis rebound urea concentration as early as 90 min. Projected (29.2+/-10.4 g) or measured (29.8+/-10.5 g) net urea removal was highly correlated with the amount of urea collected in the total spent dialysate (29.7+/-10.6 g) (R2=0.99, R2=0.97 respectively). CONCLUSIONS: These results indicate that on-line, real-time analysis of urea kinetics may provide information on delivery of adequate dialysis in high-efficiency techniques.

Adult↗

PubMed1995

Insulin resistance and hyperinsulinemia in homozygous beta-thalassemia.

Insulin resistance and hyperinsulinemia have been reported in homozygous beta-thalassemia before the development of diabetes. However, insulin sensitivity (SI) has never been studied in normoinsulinemic patients. Furthermore, whether hyperinsulinemia is due to increased beta-cell secretion or to decreased hepatic insulin extraction is poorly understood. We estimated SI, beta-cell secretion, and hepatic insulin extraction using the minimal model analysis of a frequently sampled intravenous glucose tolerance test (2.8 g/m2) in two groups of nondiabetic pubertal patients with homozygous beta-thalassemia (seven hyperinsulinemic and seven normoinsulinemic patients) and seven control subjects matched for age, body mass index, and pubertal stage. In both thalassemic groups, SI was reduced by approximately 40% (3.52 +/- 0.57 and 3.74 +/- 0.66 v 6.89 +/- 1.02 10(-4).min-1 [microU/mL], P = .011) and was inversely correlated with iron overload (r = -.707, P = .006). All parameters of beta-cell secretion were not significantly different in patients and controls. On the other hand, basal posthepatic insulin delivery (BDR) was more than doubled in hyperinsulinemic patients with respect to normoinsulinemic patients or controls (15.1 +/- 2.4 v 6.1 +/- 1.1 and 7.5 +/- 2.3 pmol/L.min-1, P = .012), and the same was true for total posthepatic insulin delivery ([TID] 6.3 +/- 1.0 v 2.9 +/- 0.5 and 2.9 +/- 0.7 pmol/L.240 min-1, P = .015). Hepatic insulin extraction was significantly lower in hyperinsulinemic patients than in normoinsulinemic patients or controls (49.3% +/- 9.4% v 73.0% +/- 3.7% and 77.4% +/- 3.9%, P = .011), and in patients it was inversely correlated with iron overload (r = -.829, P = .0001). In conclusion, insulin resistance is present even in normoinsulinemic patients, beta-cell responsiveness to glucose is normal, and hyperinsulinemia is mainly due to decreased hepatic insulin extraction. In nondiabetic thalassemic patients, these defects are possibly related to iron overload.

Adolescent↗

PubMed1995

Intravenous calcitriol normalizes insulin sensitivity in uremic patients.

Recent studies suggest that secondary hyperparathyroidism and/or vitamin D deficiency are responsible for the insulin resistance in chronic renal failure. We investigated the effect of a 12-week intravenous treatment with 1,25 dihydroxycholecalciferol on glucose metabolism in 10 hemodialysis patients compared with 10 healthy control subjects by the frequently-sampled intravenous glucose tolerance test, analyzed with the minimal model technique. Compared to control subjects, the uremic patients featured elevated levels of parathyroid hormone (432 +/- 60 vs. 41 +/- 4 ng/liter, P < 0.001), insulin resistance (insulin sensitivity index, SI: 4.9 +/- 0.8 vs. 9.5 +/- 0.9 min-1/(microU/ml), P < 0.002), increased posthepatic insulin delivery (6.48 +/- 2.48 vs. 2.73 +/- 3.14 nmol/liter in 4 hr, P < 0.001) and a reduced C-peptide fractional clearance (0.033 +/- 0.004 vs. 0.085 +/- 0.009 min-1, P < 0.0002). Following treatment with 1,25 dihydroxycholecalciferol, the parathyroid hormone levels decreased significantly to 237 +/- 30 ng/liter (P < 0.05), the insulin sensitivity index (SI: 9.6 +/- 2.2, P < 0.05) reached a value similar to that of control subjects, and posthepatic insulin delivery decreased to 4.63 +/- 0.83 nmol/liter in 4 hr (P < 0.01), while all the other parameters remained unchanged. In summary, uremic patients with secondary hyperparathyroidism were found to be severely insulin resistant and hyperinsulinemic. Intravenous vitamin D treatment led to a significant reduction of parathyroid hormone levels and to a complete normalization of insulin sensitivity in the hemodialysis patients. Thus, intravenous 1,25 dihydroxycholecalciferol improves insulin resistance in uremic patients, acting per se or by reducing secondary hyperparathyroidism.

Adult↗

PubMed1994

Role of islet amyloid polypeptide secretion in insulin-resistant humans.

Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hypertensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034 +/- 0.004 min-1 in control subjects, 0.058 +/- 0.008 in the obese and 0.050 +/- 0.008 in the hypertensive patients) was significantly different (p < 0.01) in each group compared with that of insulin (0.14 +/- 0.03 min-1) and similar to that of C-peptide (0.061 +/- 0.007 min-1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4 +/- 0.4 min-1/(microU/ml); p < 0.0005) and the obese (2.7 +/- 0.5; p < 0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1 +/- 1.3). Marked insulin hypersecretion was found in the hypertensive (57.6 +/- 5.2 nmol.l-1 in 180 min; p < 0.001) and obese (60.8 +/- 10.1; p < 0.003) patients in comparison with control subjects (32.4 +/- 3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1 +/- 16.6 pmol/l in 180 min; p < 0.02) and obese (78.6 +/- 13.1; p < 0.005) patients than in control subjects (40.5 +/- 6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Beta-cell response and insulin hepatic extraction in noncirrhotic alcoholic patients soon after withdrawal.

A decreased tolerance to carbohydrates has been reported in several studies of liver diseases, whereas only a few investigations have been performed in chronic noncirrhotic alcoholic patients with and without alcohol abstinence. The aim of this study was to evaluate in detail the metabolic portrait of six noncirrhotic alcoholics during the early phase of alcohol withdrawal by quantifying the main processes involved in glucose disappearance. Data from frequently sampled intravenous glucose tolerance tests (FSIGTs) were analyzed by means of the minimal model (MINMOD) approach, which provided measurements of the (prehepatic) beta-cell secretion and of insulin degradation in the liver, along with indexes of insulin sensitivity and glucose effectiveness. Plasma insulin levels were lower in the patients (basal, 3.5 +/- 0.2 v 8.0 +/- 1.8 in matching controls, P < .05; area under the curve, 1.41 +/- 0.07 mU/mL in 240 minutes v 4.06 +/- 0.37, P < .001), and C-peptide concentrations were higher (basal, 107 +/- 3.5 v 36 +/- 9 ng/dL in controls, P < .05; area under the curve, 492 +/- 118 ng/mL in 240 minutes v 245 +/- 66, P = .05). The model analysis confirmed the absence of a decrease beta-cell release; in fact, in the alcoholics there was a basal secretion of 19 +/- 5 versus 9 +/- 2 pmol/L/min in controls (P < .05) and a total release of 9.5 +/- 1.8 nmol/L in 240 minutes versus 6.5 +/- 1.4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Mathematical models of insulin secretion in physiological and clinical investigations.

The discovery of the radioimmunoassay for the measurement of insulin concentration stimulated several clever studies which showed, both in vitro and in vivo, the peculiar biphasic pattern of the beta-cell response to glucose stimulation. Physiologists took the challenge to describe with mathematical models those data, introducing tools that provided medical and biological research scientists with further knowledge of the nature of the complex processes involved in insulin secretion. Simulation models were therefore developed to account for the dependence on each other of the different features of the system behaviour to better understand them and to formulate hypotheses for further investigations. The disadvantages of these models (rather complex mathematical structure, unidentifiability, etc.) limited their use to a few applications, mostly as teaching tools. The use of models in the clinical setting required the individualization of the parameter set for a single subject from an experimental test as simple as possible. This led to the development of the minimal model of insulin appearance and kinetics. This model, fully identifiable, thus enables the furnishing of a personalized picture of insulin behaviour, providing insights on hormone secretion during a (frequently sampled) intravenous glucose tolerance test. However, this model analyzed systemic insulin concentration data and gave information only on post-hepatic insulin delivery. Since the liver takes up more than 50% of the released hormone, a further step was necessary to evaluate insulin secretion, i.e. the analysis of the behaviour of C-peptide, which is released equimolarly with insulin, but is not extracted by the liver. The last generation models are in fact descriptors of the systemic C-peptide dynamics, and are used to reconstruct its secretion which is assumed to be molarly equal to that of insulin. Mainly three models of pre-hepatic insulin appearance, based on this principle, have been developed and used in clinical studies.

C-Peptide↗

PubMed1994

Increased levels of circulating islet amyloid polypeptide in patients with chronic renal failure have no effect on insulin secretion.

To elucidate the metabolism of islet amyloid polypeptide (IAPP) with respect to a possible renal elimination we investigated IAPP levels in 20 lean, nondiabetic patients with renal failure maintained on chronic hemodialysis (HD) and in 20 healthy controls. The basal levels of IAPP were significantly higher in uremic patients than in controls (15.1 +/- 3.2 vs. 3.2 +/- 0.2 pM, P < 0.001) suggesting renal excretion of IAPP. To investigate the impact of chronically elevated levels of endogenous IAPP on insulin secretion and insulin sensitivity, a frequently sampled intravenous glucose tolerance test (FSIGT) was performed in a subset of patients on hemodialysis and in age-matched healthy controls (C) and obese patients with normal (NGT) and with impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was 8.7 +/- 1.5 in C (P < 0.05 vs. NGT, P < 0.01 vs. IGT), 5.4 +/- 0.9 in HD (P < 0.05 vs. IGT), 3.1 +/- 1.0 in NGT, and 2.0 +/- 0.5 in IGT. First phase insulin secretion was increased in patients on HD compared with those of several control groups. The results of this study therefore indicate a renal route of metabolism of IAPP. Increased endogenous circulating IAPP levels over a long period of time do not lead to a decrease in insulin release in patients on HD and do not cause the insulin resistance commonly seen in obesity and diabetes. Increased levels of circulating IAPP therefore are not likely to be a pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM).

Adult↗

PubMed1993

Effect of dexamethasone on insulin sensitivity, islet amyloid polypeptide and insulin secretion in humans.

The response of islet amyloid polypeptide and insulin and their molar ratios were investigated in eight healthy volunteers before and after treatment with dexamethasone by oral and frequently-sampled intravenous glucose tolerance tests. Following dexamethasone treatment the insulin sensitivity index decreased significantly from 6.5 +/- 1.3 to 4.1 +/- 1.0 (microU.ml-1).min-1, p < 0.05. The area under the curve representing above-basal levels of insulin during oral glucose tolerance test increased significantly following dexamethasone treatment from 48132 +/- 9736 to 82230 +/- 14846 pmol.l-1 x 3 h-1, p < 0.05, the area under the curve of islet amyloid polypeptide increased from 1308 +/- 183 to 2448 +/- 501 pmol.l-1 x 3 h-1, p < 0.05. The overall insulin/islet amyloid polypeptide molar ratios calculated from the area under the curve during the 3-h period of the oral glucose tolerance test was not significantly different before and after dexamethasone treatment (42 +/- 5 vs 40 +/- 4). During the oral glucose tolerance test the insulin/islet amyloid polypeptide ratio increased significantly from baseline to 30 min (p < 0.05), then declined towards initial values before and after dexamethasone treatment. In conclusion, dexamethasone induced a significant decrease in insulin sensitivity and a significant increase in insulin secretion during the oral glucose tolerance test. However, in contrast to previous animal experiments we did not find a change in the insulin/islet amyloid polypeptide ratio before and after dexamethasone treatment.

Adult↗