G. Pacini

Increased plasma leptin in gestational diabetes

Aims/hypothesis. Insulin resistance as well as marked changes in body weight and energy metabolism are associated with pregnancy. Its impact on plasma leptin is not known and was determined in this longitudinal study in both diabetic and normal pregnancy. Methods. At 28 gestational weeks plasma concentrations of leptin and B-cell hormones were measured at fasting and after an oral glucose load (OGTT:75 g) in women with gestational diabetes and pregnant women with normal glucose tolerance and compared with women who were not pregnant (C). Results. Plasma leptin (ng/ml) was higher (p < 0.001) in women with gestational diabetes (24.9 ± 1.6) than in women with normal glucose tolerance (18.2 ± 1.5) and increased in both groups when compared with the non-pregnant women (8.2 ± 1.3; p < 0.0005). No change in plasma leptin concentrations was induced by OGTT in any group. Basal insulin release was higher (p < 0.05) in women with gestational diabetes compared with the pregnant women with normal glucose tolerance. Marked insulin resistance was confirmed by a 20 % lower (p < 0.05) insulin sensitivity in subgroup analysis and a decrease of almost 40 % in fasting glucose/insulin ratio (p < 0.005) in women with gestational diabetes. Leptin correlated in women with gestational diabetes with basal plasma concentrations of glucose (p < 0.02), insulin (p < 0.004) and proinsulin (p < 0.01) as well as with BMI (p < 0.001) and overall pregnancy induced maternal weight gain (p < 0.009). With normalisation of blood glucose 8 weeks after delivery in women with gestational diabetes their plasma leptin decreased (p < 0.0005) to 17.3 ± 1.9 ng/ml but did not completely normalize (p < 0.05 vs non-pregnant women). Conclusion/interpretation. Our data show that women with gestational diabetes without any change in plasma leptin upon oral glucose loading have increased plasma leptin concentrations during and after pregnancy, a clear association of plasma leptin with the respective concentration of glucose and insulin resistance as well as with changes in body weight, and a failure to normalize spontaneously BMI to the same extent as pregnant women with normal glucose tolerance when compared with matched control subjects. [Diabetologia (2001) 44: 164–172]

Role of islet amyloid polypeptide secretion in insulin-resistant humans

SummaryAlthough 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 hyper-tensive 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/(μU/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 · 1−1 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/1 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. We conclude that, due to a significantly slower clearance of islet amyloid polypeptide in comparison to insulin, reliance on molar ratios between these two peptides might be misleading in the interpretation of islet amy-loid polypeptide secretion especially under non-steady-state conditions.

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 (β-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/1) versus control subjects (27 ± 1 pmol/1) (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 · 1−1 · 3 h−1; NGT subjects, 166 ± 31 pmol · 1−1 · 3 h−1; control subjects, 40 ± 1 pmol · 1−1 · 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 · 1−1 · 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) proinsulinto-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/1, 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-toinsulin 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.

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

SummaryThe 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 (μU·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−1·3 h−1, p<0.05, the area under the curve of islet amyloid polypeptide increased from 1308±183 to 2448±501 pmol·l−1·3h−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 sensivity 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.

β-Cell hypersecretion and not reduced hepatic insulin extraction is the main cause of hyperinsulinemia in obese nondiabetic subjects

Obesity is characterized by peripheral hyperinsulinemia, for which either beta-cell hypersecretion, diminished hepatic insulin extraction, or both may be responsible. To clarify this issue, we investigated insulin secretion and hormone hepatic extraction in 18 nondiabetic obese patients (body mass index [BMI], 39 +/- 1.3 kg/m2) and 18 healthy, lean control subjects (BMI, 21.3 +/- 0.7 kg/m2). Body fat distribution was calculated by measuring the waist to hip ratio (WHR). A highly reduced tissue insulin sensitivity (2.4 +/- 0.5 v 9.5 +/- 1.5 10(4).min-1/[microU/mL], P > .0005) and glucose effectiveness, ie, glucoses ability to stimulate its own disappearance at basal insulin (16 +/- 2 v 30 +/- 3 10(3).min-1, P > .005), were found in the overweight subjects compared with the controls. The basal (76 +/- 14 v 37 +/- 4 pmol/L/min) and total (377,848 +/- 5,562 v 16,864 +/- 1,850 pmol/L) prehepatic insulin secretion and the basal (15 +/- 2 v 7 +/- 0.7 pmol/L/min) and total (8,286 +/- 2,009 v 2,840 +/- 210 pmol/L) posthepatic insulin delivery were significantly higher in the overweight subjects compared with the controls (P < .005), whereas the mean hepatic insulin extraction did not differ (77.8% +/- 2.6% v 79.5% +/- 2.6%). A significant inverse correlation was found between the hepatic insulin extraction and the WHR (r = .5, P > .04), signifying the importance of fat distribution in insulin metabolism. The obese patients were subdivided into two subgroups according to their glucose tolerance; eight patients exhibited a normal tolerance and the remaining 10 were intolerant.(ABSTRACT TRUNCATED AT 250 WORDS)

β-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.

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.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 β-cell hormone amylin. We therefore performed an intravenous injection of 50 μg of human synthetic amylin (amlintide) in nine healthy male subjects during suppression of endogenous amylin release by intravenous somatostatin (0.06 μg ⋅ 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-1and 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.

Elevated hepatic insulin extraction in essential hypertension.

Insulin resistance, hyperinsulinemia, and dyslipidemia are common characteristics of patients with untreated hypertension. However, the link between the vascular and metabolic disturbances is still unclear. To provide further insights into the metabolic picture of subjects with hypertension, we evaluated insulin resistance, pancreatic secretion, and hepatic extraction of the hormone in 16 untreated patients with essential hypertension before and after 12-16 weeks of drug treatment in comparison with 16 age-, sex-, and body weight-matched normotensive control subjects. All subjects underwent an oral and a frequently sampled intravenous glucose tolerance test. Metabolic parameters were calculated by the minimal model technique. The hypertensive patients exhibited a highly reduced tissue insulin sensitivity (2.6 +/- 0.4 versus 9.6 +/- 1.9 10(4) min-1/[microunits/mL]; p < 0.001). The basal secretion rate (70 +/- 11 versus 35 +/- 5 pmol/L per minute) and the total amount of prehepatically secreted insulin (32 +/- 4 versus 16 +/- 2 nmol/L in 4 hours) were significantly increased in the hypertensive patients compared with the control subjects (p < 0.01), whereas the posthepatic insulin delivery rate was not significantly different between the two groups (4.9 +/- 0.6 versus 3.5 +/- 0.3 nmol/L in 4 hours). Hepatic insulin extraction was found to be significantly elevated in the hypertensive patients compared with control subjects (81 +/- 4% versus 69 +/- 3%, p < 0.04). Increased hepatic insulin extraction partially ameliorated B cell hypersecretion in hypertensive patients. After 12-16 weeks of drug treatment, the blood pressure was normalized, but the metabolic profile of the patients remained unchanged. We conclude that elevated insulin extraction in the liver is a specific characteristic of individuals with essential hypertension and partially compensates pancreatic B cell hypersecretion.

Value of the intravenous and oral glucose tolerance tests for detecting subtle impairments in insulin sensitivity and beta-cell function in former gestational diabetes

Objective  Women with former gestational diabetes mellitus (fGDM) often show defects in both insulin sensitivity and beta‐cell function but it is not clear which defect plays the major role or which appears first. This might be because fGDM women are often studied as a unique group and not divided according to their glucose tolerance. Different findings might also be the result of using different tests. Our aim was to study insulin sensitivity and beta‐cell function with two independent glucose tolerance tests in fGDM women divided according to their glucose tolerance.

Non-esterified fatty acid dynamics during oral glucose tolerance test in women with former gestational diabetes

Diabet. Med. 29, 351–358 (2012)