Increments In Plasma Insulin Research Articles

Effect of inulin on breath hydrogen, postprandial glycemia, gut hormone release, and appetite perception in RYGB patients: a prospective, randomized, cross-over pilot study

Background and objectiveLarge intestinal fermentation of dietary fiber may control meal-related glycemia and appetite via the production of short-chain fatty acids (SCFA) and the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We investigated whether this mechanism contributes to the efficacy of the Roux-en-Y gastric bypass (RYGB) by assessing the effect of oligofructose-enriched inulin (inulin) vs. maltodextrin (MDX) on breath hydrogen (a marker of intestinal fermentation), plasma SCFAs, gut hormones, insulin and blood glucose concentrations as well as appetite in RYGB patients.MethodEight RYGB patients were studied on two occasions before and ~8 months after surgery using a cross-over design. Each patient received 300 ml orange juice containing 25 g inulin or an equicaloric load of 15.5 g MDX after an overnight fast followed by a fixed portion snack served 3 h postprandially. Blood samples were collected over 5 h and breath hydrogen measured as well as appetite assessed using visual analog scales.ResultsSurgery increased postprandial secretion of GLP-1 and PYY (P ≤ 0.05); lowered blood glucose and plasma insulin increments (P ≤ 0.05) and reduced appetite ratings in response to both inulin and MDX. The effect of inulin on breath hydrogen was accelerated after surgery with an increase that was earlier in onset (2.5 h vs. 3 h, P ≤ 0.05), but less pronounced in magnitude. There was, however, no effect of inulin on plasma SCFAs or plasma GLP-1 and PYY after the snack at 3 h, neither before nor after surgery. Interestingly, inulin appeared to further potentiate the early-phase glucose-lowering and second-meal (3–5 h) appetite-suppressive effect of surgery with the latter showing a strong correlation with early-phase breath hydrogen concentrations.ConclusionRYGB surgery accelerates large intestinal fermentation of inulin, however, without measurable effects on plasma SCFAs or plasma GLP-1 and PYY. The glucose-lowering and appetite-suppressive effects of surgery appear to be potentiated with inulin.

Long-Term Follow-up of β-Transfusion-Dependent Thalassemia (TDT) Normoglycemic Patients with Reduced Insulin Secretion to Oral Glucose Tolerance Test (OGTT): A Pilot Study.

ObjectiveTo study the endocrine pancreas’ function in transfusion-dependent β-thalassemia (β-TDT) patients with a normal glucose tolerance test (NGT) and hypoinsulinemia. In addition, the prospective long–term follow-up using an annual oral glucose tolerance test (OGTT) to detect any abnormality of glucose metabolism.Patients and methodsSeven β-TDT patients (mean age 22.4 ± 4.2 years) with NGT and inadequate insulin response (hypoinsulinemia) to OGTT were referred for a second opinion to an Italian Centre.ResultsThe first-phase insulin response (FPIR), expressed as the sum of 1 and 3 minutes insulin, to intravenous glucose tolerance test (IVGTT), was between the 1st and 3rd percentile in two patients and between the 3rd and 10th percentile in five. The results were not associated with β-cell autoimmunity. After 43 ± 26 months (range 11 – 80 months) of follow-up, two patients developed impaired glucose tolerance (IGT), three both IGT and impaired fasting glucose (IFG) and two overt diabetes mellitus (DM). Interestingly, the patients who developed DM had, at baseline, the lowest value of the insulinogenic index (IGI: 0.08 and 0.25), defined as the ratio of the increment of plasma insulin to plasma glucose during the first 30 minutes after OGTT. Moreover, a significant correlation was found between the IGI at baseline and at follow-up in the patients who developed IGT with or without IFG (R= 0.927; P: 0.023). A significant reduction of Matsuda insulin sensitivity index (ISIM) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) was documented in the study cohort at the diagnosis of IFG, IGT, and DM. There was a significant inverse correlation between ISSI-2 and area under the curve plasma glucose (AUC-PG).ConclusionsThese data demonstrated, for the first time, progressive deterioration in glucose homeostasis in β-TDT subjects with NGT and hypoinsulinemia and that the ISSI-2 index may be a valuable parameter to identify patients at high risk for developing glucose dysregulation.

Evaluation of a Reduced Sampling Schedule for Assessment of Pancreatic Beta‐Cell Function with the Intravenous Glucose Tolerance Test During a Dietary Intervention

Pancreatic beta‐cell function is a key determinant of glucose tolerance. The intravenous glucose tolerance test (IVGTT) can be used to assess both the insulin sensitivity index (Si) and the acute insulin response to glucose (AIRg). The disposition index (DI = Si × AIRg) reflects the adequacy of pancreatic beta‐cell response for the level of insulin sensitivity. The aim of this analysis was to compare the AIRg and DI values calculated using a reduced early test sampling schedule (t = 0, 5, 10 min), to those from the full sampling schedule (t = 0, 3, 5, 7, and 10 min). Participants included men (n = 8) and women (n = 16) with mean (SD) age 48.9 (9.9) y and body mass index 30.8 (4.9) kg/m2. Subjects consumed 0, 15, and 30 g/d high‐amylose resistant starch (RS) for 4 weeks each, in a double‐blind, randomized, crossover trial, and underwent a 180‐min IVGTT at the end of each treatment period. The Minmod Millenium program was used to derive Si. AIRg was calculated as the mean increment in plasma insulin during the first 10 min of the test for the full and reduced sampling schedules. The median (interquartile range) full schedule AIRg values during the control, 15, and 30 g/d RS conditions were 43 (29, 103), 47 (23, 67) and 44 (30, 94) mU/L, respectively. Mean (95% confidence interval) percentages of the full schedule values for the reduced schedule values were 82 (79–86), 87 (76–98) and 83 (80–85) for the control, 15 and 30 g/d RS conditions, respectively, all p < 0.05 vs. the full schedule. Correlations between the AIRg and DI values from the two schedules during each RS condition were high (Pearson r values all ≥0.98, p < 0.001). Thus, although AIRg and DI values cannot be directly compared between sampling schedules, the reduced sampling schedule accurately reflects relative AIRg and DI values, and may thus be a time and cost‐effective option when conducting the IVGTT in clinical and epidemiological studies.Support or Funding InformationIngredion Inc., Westchester, IL

Role of Adipose Tissue Insulin Resistance in the Natural History of Type 2 Diabetes: Results From the San Antonio Metabolism Study.

In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of this study was to evaluate the role of resistance to the antilipolytic effect of insulin (adipose tissue IR [Adipo-IR]) in a large group of subjects with NGT, impaired glucose tolerance (IGT), and T2DM. Three hundred two subjects with varying glucose tolerance received an oral glucose tolerance test (OGTT) and euglycemic insulin clamp. We evaluated Adipo-IR (fasting and mean OGTT plasma free fatty acid [FFA] × insulin concentrations), peripheral IR (1/[Matsuda index] and (M/I)-1 value), and β-cell function (calculated as the ratio of the increment in plasma insulin to glucose [OGTT/IR (ΔI/ΔG ÷ IR)]). Fasting Adipo-IR was increased twofold in obese subjects with NGT and IGT versus lean subjects with NGT (8.0 ± 1.1 and 9.2 ± 0.7 vs. 4.1 ± 0.3, respectively) and threefold in subjects with T2DM (11.9 ± 0.6; P < 0.001). Progressive decline in ΔI/ΔG ÷ IR was associated with a progressive impairment in FFA suppression during OGTT, whereas the rise in mean plasma glucose concentration only became manifest when subjects became overtly diabetic. The progressive decline in β-cell function that begins in individuals with NGT is associated with a progressive increase in FFA and fasting Adipo-IR.

Evaluation of an Insulin Sensitivity Index from the Short Intravenous Glucose Tolerance Test

The aim of this analysis was to compare insulin sensitivity indices calculated from a short (50 min), insulin‐modified intravenous glucose tolerance test (IVGTT; Tura SI) to that from a full 180 min IVGTT using minimal model analysis (MM SI), as well as the Matsuda Index (M‐SI) from a 120 min liquid meal tolerance test (Maki et al. Diabetes Tech Ther 2011;13:661–6). The IVGTT included glucose (0.3 g/kg, t = 0 min) and regular human insulin (0.03 U/kg; t = 20 min) injection with samples collected at frequent intervals over 180 min. Tura SI was calculated as the fractional glucose disappearance rate/average increment in plasma insulin, both from 10–50 min. The MINMOD MILLENNIUM program (v6.02) was used to calculate MM SI. Subjects were overweight or obese men (n = 8) and women (n = 16) without diabetes who agreed to participate in a substudy after completing a dietary intervention trial. Mean ± SEM MM SI was 3.94 ± 3.38 × 10−4 L*min−1*mU−1, age was 48.9 ± 2.0 y and body mass index was 30.8 ± 0.6 kg/m2. Pearson correlation coefficients were: Tura SI with MM SI r = 0.963, Tura SI with M‐SI r = 0.803, and MM SI with M‐SI r = 0.776, all p &lt; 0.001. Thus, Tura SI from the first 50 min of an insulin‐modified IVGTT correlates very strongly with 180 min MM SI (reference method), and the relationship between Tura SI with M‐SI was similar in magnitude to that between MM SI and M‐SI. These results suggest that the short IVGTT may be used as a less costly and time‐consuming alternative to the 180 min IVGTT for assessment of whole‐body insulin sensitivity.Support or Funding InformationIngredion, Westchester, IL

Dipeptidyl peptidase IV inhibitory activity of protein hydrolyzates from &lt;i&gt;Amaranthus hypochondriacus&lt;/i&gt; L. Grain and their influence on postprandial glycemia in Streptozotocin-induced diabetic mice.

Background: Type 2 diabetes is a chronic metabolic disorder. Recently, dipeptidyl peptidase IV (DPP-IV) inhibitors that protect incretin hormones from being cleaved by DPP-IV have been used as drugs to control glycemia. This study examined the potential hypoglycemic effect of amaranth grain storage protein hydrolyzates to control postprandial glycemia in streptozotocin (STZ)-induced diabetic mice as a model system of diabetes, and their inhibition mode on the enzyme. Material and Methods : Amaranth grain proteins were isolated and hydrolyzed and fractionated by gel filtration. The DPP-IV inhibitory activity of hydrolyzates as well as their kinetic parameters were assessed. Selected hydrolyzates (300 mg/kg body weight) were administered in a single administration-study (SAS) or in the same concentration during a four-week chronic daily dosing study (FWCDDS) in order to observe the effect on postprandial glycemia of diabetic mice. Results : Albumin 1, Globulin and Glutelin hydrolyzates (GluH) competitively inhibited DPP-IV in vitro (Ki= 0.11-5.61 mg/mL). GluH called Glu.III (IC 50 = 0.12±0.01 mg/mL) considerably inhibited DPP-IV activity. GluH identified as GluH24 improved glucose tolerance significantly (p<0.05), with remarkable increments in plasma insulin in SAS and FWCDDS (1.25 and 2.25 mg/mL, respectively). This effect could be compared to the one obtained from the mice group that was administered Sitagliptin (580 mg/kg body weight) as positive control (p<0.05). Conclusion : Amaranth Glutelin hydrolyzates yielded the highest enzyme inhibitory activity reported not only in vitro, but also in the STZ-induced diabetic mice in order to control postprandial glycemia. Key words : Amaranth protein hydrolyzate, DPP-IV inhibitory activity, diabetes

Beyond fasting plasma glucose: The association between coronary heart disease risk and postprandial glucose, postprandial insulin and insulin resistance in healthy, nondiabetic adults

ObjectivePrediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals. MethodsPlasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile. ResultsFor purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p<0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals. ConclusionsIn nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.

High-Fat Food, Sympathetic Nerve Activity, and Hypertension

See related article, pp 1498–1502 Obesity is a rapidly escalating epidemic accounting for more than $150 billion per year in healthcare expenditures in the United States, more than any other medical condition. The consequences are severe. Obese humans exhibit increased incidence of type II diabetes mellitus, obstructive sleep apnea, hypertension, and regionally specific sympathoexcitation, in particular to the kidneys and legs.1–4 However, whether increased sympathetic nerve activity (SNA) is a cause or a consequence of obesity has been debated.3 Moreover, although obesity-induced hypertension is associated with increased SNA, the mechanisms are unclear.1–4 Two recent articles5,6 in Hypertension address these questions by characterizing the time course of the increases in SNA, monitored using telemetry, as lean animals initiate a high-fat diet (HFD). In the article by Armitage et al,5 male New Zealand white rabbits were instrumented for telemetric recordings of arterial pressure (AP) and renal SNA (RSNA). One week later, blood samples were collected for the measurements of glucose, insulin, and leptin, and basal levels of AP, heart rate (HR), and RSNA were measured in the laboratory. Rabbits were then randomized into 2 groups: 1 group was fed 110 g/d of standard rabbit chow (4.2% fat) and the other 190 g/d of a HFD (standard diet with 13.3% fat). Weekly measurements continued for 3 weeks and after a 1-week recovery period. After 1 week, HFD-fed rabbits exhibited elevations in AP (by 6%), HR (by 11%), and RSNA (by ≈50%), in association with increments in body weight, fat mass, and plasma glucose, insulin, and leptin levels. The increases in HR, RSNA, glucose, insulin, and leptin remained level for the subsequent 2 weeks, whereas body weight and AP increased further. Interestingly, during the recovery period, glucose, insulin, leptin, and HR returned to …

Glucocorticoid overexposure in neonatal life alters pancreatic beta-cell function in newborn foals1

Studies in humans and animals have linked abnormal programming of adult tissue function to excess glucocorticoids during perinatal development. The current study investigated the hypothesis that physiological variations in glucocorticoid concentrations during early neonatal life of the foal alter the secretory responses of the pancreatic β cells 2 and 12 wk after treatment. Spontaneously delivered foals received either saline or long-acting ACTH for 5 d from 1 d after birth to maintain an endogenous rise in cortisol concentrations. Starting at d 10, pancreatic β cell function was studied using an intravenous (i.v.) glucose tolerance test, an i.v. arginine challenge, and an i.v. tolbutamide challenge. The maximum increment in plasma insulin achieved in response to exogenous glucose was less in ACTH-treated foals at both 2 and 12 wk of age (P<0.05). By 12 wk of age, developmental changes also occurred in the magnitude and biphasic pattern of glucose-stimulated insulin release. The area under the insulin curve during the early phase of insulin secretion (0 to 30 min) was not different between the 2- and 12-wk-old animals but was significantly greater during the later phase (30 to 120 min) at 12 wk than at 2 wk (P<0.05). Arginine infusion induced a brief 5 to 15 min increase in plasma concentrations of insulin that was not different in saline- and ACTH-treated foals. The β-cell response to tolbutamide infusion was rapid and monophasic, and there was no difference (P>0.05) in the area under the insulin curve with treatment at 2 or at 12 wk. However, after tolbutamide, plasma insulin concentrations remained increased for a longer period in the ACTH-treated than in the saline-treated foals at 12 wk of age (P<0.05). Hence, this is the first study to show altered pancreatic β-cell function after ACTH-induced glucocorticoid overexposure during early postnatal life in foals.

Opuntia Ficus-Indica Ingestion Stimulates Peripheral Disposal of Oral Glucose Before and After Exercise in Healthy Men

The purpose of this study was to investigate the effect of Opuntia ficus-indica (OFI) cladode and fruit-skin extract on blood glucose and plasma insulin increments due to high-dose carbohydrate ingestion, before and after exercise. Healthy, physically active men (n = 6; 21.0 ± 1.6 years, 78.1 ± 6.0 kg) participated in a double-blind placebo-controlled crossover study involving 2 experimental sessions. In each session, the subjects successively underwent an oral glucose tolerance test at rest (OGTT(R)), a 30-min cycling bout at ~75% VO(2max), and another OGTT after exercise (OGTT(EX)). They received capsules containing either 1,000 mg OFI or placebo (PL) 30 min before and immediately after the OGTT(R). Blood samples were collected before (t₀) and at 30-min intervals after ingestion of 75 g glucose for determination of blood glucose and serum insulin. In OGTT(EX) an additional 75-g oral glucose bolus was administered at t₆₀. In OGTT(R), OFI administration reduced the area under the glucose curve (AUC(GLUC)) by 26%, mainly due to lower blood glucose levels at t₃₀ and t₆₀ (p < .05). Furthermore, a higher serum insulin concentration was noted after OFI intake at baseline and at t₃₀ (p < .05). In OGTT(EX), blood glucose at t₆₀ was ~10% lower in OFI than in PL, which resulted in a decreased AUC(GLUC) (-37%, p < .05). However, insulin values and AUC(INS) were not different between OFI and PL. In conclusion, the current study shows that OFI extract can increase plasma insulin and thereby facilitate the clearance of an oral glucose load from the circulation at rest and after endurance exercise in healthy men.

Contributions of fat and protein to the incretin effect of a mixed meal

The relative contributions of fat and protein to the incretin effect are still largely unknown. This study assessed the incretin effects elicited by a mixed meal, and by its fat and protein components alone, with the use of a hyperglycemic clamp combined with oral nutrients. Eight healthy volunteers were studied over 6 h after ingestion of a sandwich containing 1) dried meat, butter, and white bread; 2) dried meat alone; 3) butter alone; or 4) no meal (fasting control). Meals were ingested during a hyperglycemic clamp, and the incretin effect was calculated as the increment in plasma insulin after food intake relative to the concentrations observed during the control study. A significant augmentation of postprandial insulin secretion, independent of plasma glycemia, occurred after ingestion of the mixed nutrients and the lipid component of the mixed meal (203 ± 20.7% and 167.4 ± 22.9% of control, respectively; both P < 0.05), whereas the protein component did not induce a significant incretin effect (129.0 ± 7.9% of control; P = 0.6) Fat ingestion, in an amount typical of a standard meal, increases insulin secretion during physiologic hyperglycemia and thus contributes to the incretin effect. In contrast, ingestion of protein typical of normal meals does not contribute to the augmentation of postprandial insulin secretion. This trial was registered at clinicaltrials.gov as NCT00869453.

Serum retinol‐binding protein 4 is associated with insulin secretion in Chinese people with normal glucose tolerance

Serum levels of retinol-binding protein 4 (RBP4) are associated with insulin resistance and type 2 diabetes mellitus (T2DM) and may impact on β-cell function. Thus, the present study investigated the relationship between serum RBP4 and insulin secretion in Chinese people with and without T2DM. A 75 g oral glucose tolerance test was administered to all 867 subjects and serum RBP4 concentrations were determined. Insulin secretion was assessed by ΔI/ΔG (increment in plasma insulin concentration/plasma glucose concentration 30 min after the oral administration of 75 g glucose) and the total area under the curve for insulin over 180 min (AUC-I). Magnetic resonance imaging was used to measure visceral fat area (VFA) at L4-L5; subjects with VFA ≥80 cm(2) were considered to have visceral obesity (VO). Serum RBP4 concentrations were significantly higher in subjects with VO than without, regardless of the presence of T2DM. In addition, in the entire group with normal glucose tolerance (NGT), serum RBP4 was positively correlated with ΔI/ΔG (r = 0.152; P < 0.01) and AUC-I (r = 0.218; P < 0.01) after adjustment for gender. The correlation between RBP4 and ΔI/ΔG (r = 0.162; P < 0.05) and AUC-I (r = 0.195; P < 0.01) remained in NGT non-VO subjects. No correlation was found between serum RBP4 and ΔI/ΔG or AUC-I in T2DM patients. Stepwise multiple regression analysis showed that serum RBP4 is an independent factor that contributes to ΔI/ΔG (β = 0.176) and AUC-I (β = 0.204) in NGT non-VO subjects. Serum RBP4 is correlated with glucose-stimulated insulin secretion in NGT non-VO subjects, but not in NGT VO subjects and T2DM patients.

Risk of Progression to Type 2 Diabetes Based on Relationship Between Postload Plasma Glucose and Fasting Plasma Glucose

We sought to assess the risk of progression to type 2 diabetes in normal glucose tolerance (NGT) subjects based on the relationship between the plasma glucose concentration during oral glucose tolerance tests (OGTTs) and the fasting plasma glucose (FPG) concentration. Subjects with NGT (n = 1,282) from the San Antonio Heart Study received an OGTT with measurement of the plasma glucose concentration at 0, 30, 60, and 120 min at baseline and after 7-8 years of follow-up. Subjects were divided into four groups based on the relationship between the plasma glucose concentration during the OGTT and the FPG concentration on the same day as the OGTT. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Early-phase insulin secretion was calculated as the ratio between the incremental plasma insulin and glucose concentrations during the first 30 min of the OGTT (DeltaI(0-30)/DeltaG(0-30)). Total insulin secretion was calculated as the ratio between the incremental areas under the insulin and glucose curves during the OGTT [DeltaG(AUC)/DeltaI(AUC)]. In 23 subjects (group I), the plasma glucose concentration during the OGTT returned to levels below the FPG concentration at 30 min; in 111 subjects (group II) and in 313 subjects (group III), the plasma glucose concentration during the OGTT returned to levels below the FPG concentration at 60 and 120 min, respectively. In the remaining 835 subjects (group IV), the plasma glucose concentration during the OGTT never fell below the FPG concentration. Insulin resistance, measured by HOMA-IR and the Matsuda index, increased progressively from group I through group IV, while insulin secretion measured by DeltaI(0-30)/DeltaG(0-30) and DeltaG(AUC)/DeltaI(AUC) decreased progressively from group I through group IV. The incidence of type 2 diabetes was 0% in group I and progressively increased to 0.9% in group II, 3.2% in group III, and 6.4% in group IV. Subjects whose postload plasma glucose concentration returned to baseline (i.e., FPG level) more quickly had greater insulin sensitivity, a higher insulinogenic index, and a lower risk of developing type 2 diabetes after 8 years of follow-up compared with subjects whose postload glucose concentration returned to baseline more slowly.

Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity

Glucocorticoids hypersensitivity may be involved in the development of abdominal obesity and insulin resistance. Eight normal weight and eight obese women received on two occasions a 3-h intravenous infusion of saline or hydrocortisone (HC) (1.5 microg x kg(-1) x min(-1)). Plasma cortisol, insulin, and glucose levels were measured every 30 min from time(-30) (min) (time(-30)) to time(240). Free fatty acids, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were measured at time(-30), time(180), and time(240). At time(240), subjects underwent an insulin tolerance test to obtain an index of insulin sensitivity (K(ITT)). Mean(30-240) cortisol level was similar in control and obese women after saline (74 +/- 16 vs. 75 +/- 20 microg/l) and HC (235 +/- 17 vs. 245 +/- 47 microg/l). The effect of HC on mean(180-240) insulin, mean(180-240) insulin resistance obtained by homeostasis model assessment (HOMA-IR), and K(ITT) was significant in obese (11.4 +/- 2.0 vs. 8.2 +/- 1.3 mU/l, P < 0.05; 2.37 +/- 0.5 vs. 1.64 +/- 0.3, P < 0.05; 2.81 +/- 0.9 vs. 3.32 +/- 1.02%/min, P < 0.05) but not in control women (3.9 +/- 0.6 vs. 2.8 +/- 0.5 mU/l; 0.78 +/- 0.1 vs. 0.49 +/- 0.1; 4.36 +/- 1.1 vs. 4.37 +/- 1.2%/min). In the whole population, the quantity of visceral fat, estimated by computerized tomography scan, was correlated with the increment of plasma insulin and HOMA-IR during HC infusion [Delta mean(30-240) insulin (r = 0.61, P < 0.05), Delta mean(30-240) HOMA-IR (r = 0.66, P < 0.01)]. The increase of PAI-1 between time(180) and time(240) after HC was higher in obese women (+25%) than in controls (+12%) (P < 0.05), whereas no differential effect between groups was observed for free fatty acids or adiponectin. A moderate hypercortisolism, equivalent to that induced by a mild stress, has more pronounced consequences on insulin sensitivity in abdominally obese women than in controls. These deleterious effects are correlated with the amount of visceral fat.

Short-term and Long-term Effects of Guar on Postprandial Plasma Glucose, Insulin and Glucagon-like Peptide 1 Concentration in Healthy Rats

Ingestion of guar gum decreases postprandial glycemia and insulinemia and improves sensitivity to insulin in diabetic patients and several animal models of diabetes. The aim of the present study was to compare the short-term and long-term effects of guar on plasma insulin and glucagon-like peptide 1 concentration in healthy rats. In the short-term experiments, the concomitant intragastric administration of glucose and guar reduced the early increment in plasma glucose, insulin and glucagon-like peptide 1 concentration otherwise induced by glucose alone. Comparable findings were made after twelve days of meal training exposing the rats to either a control or guar-enriched diet for fifteen minutes. Mean plasma glucose concentrations were lower while mean insulin concentrations were higher in the guar group than in the controls according to intragastric glucose tolerance tests conducted in overnight fasted rats maintained for 19 to 36 days on either the control or guar-enriched diet. The intestinal content of glucagon-like peptide 1 at the end of the experiments was also lower in the guar group. Changes in body weight over 62 days of observation were comparable in the control and guar rats. Thus, long-term intake of guar improves glucose tolerance and insulin response to glucose absorption, without improving insulin sensitivity, in healthy rats.

HMG-CoA Reductase Inhibitors Do Not Improve Glucose Intolerance in Spontaneously Diabetic Goto-Kakizaki Rats

We examined whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve glucose intolerance in spontaneously diabetic Goto-Kakizaki (GK) rats or not. The fasting blood glucose, plasma insulin, and serum cholesterol levels were significantly higher in GK rats than those in age-matched Wistar rats. All rats were given orally once a day 0.5% carboxymethylcellulose, pravastatin 8 mg/kg, simvastatin 8 mg/kg, or atorvastatin 8 mg/kg. An oral glucose tolerance test (OGTT) was performed before and 3, 6 and 12 weeks after statin treatments. The hyperglycemic response to OGTT in GK rats significantly exceeded that in Wistar rats. The plasma insulin level in GK rats increased with age until 14-week-old (treated for 6 weeks), and then decreased. Glucose intake significantly increased the plasma insulin in almost all rats. The increment of plasma insulin due to OGTT in GK rats appeared to be less than that in Wistar rats, because the basal level was already high in GK rats. Pravastatin, simvastatin, and atorvastatin did not modify changes in blood glucose and plasma insulin induced by glucose intake. In conclusion, long-term treatments of GK rats with statins did not improve glucose intolerance observed during OGTT.

K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent

Dipeptidyl peptidase IV inhibitors are expected to be categorized in a new type of antidiabetic drugs. We had developed a long-acting dipeptidyl peptidase IV inhibitor, K579 [( S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile]. The aim of present study was to characterize the pharmacological profiles of K579. In normal rats, K579 suppressed the blood glucose elevation after an oral glucose tolerance test with the increment of plasma insulin and active forms of glucagon-like peptide-1 (GLP-1). During repetitive glucose loading using Zucker fatty rats, pretreatment with K579 attenuated the glucose excursion after the second glucose loading as well as the first glucose loading without inducing hypoglycemia. The kinetic study using cell extract revealed that K579 was a more potent and slower binding inhibitor than the existing dipeptidyl peptidase IV inhibitor (NVP-DPP728, 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-( S)-pyrrolidine). These profiles of K579 might be advantageous over the existing dipeptidyl peptidase IV inhibitor with respect to less dosing frequency.

Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

BackgroundElevated non-esterified fatty acids (NEFA) concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL), 105 and 135 days gestational age (dGA, term 147+/- 3 days).MethodsThe plasma concentrations of insulin, growth hormone (GH) and ovine placental lactogen (oPL) were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA.ResultsMaternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC) profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p < 0.001 and P < 0.001, respectively). In hyperglycaemic clamp studies, while maintaining glucose levels not different from NPNL ewes, pregnant ewes displayed significantly reduced insulin responses and a maintained depressed insulin secretion. In NPNL ewes, 105 and 135 dGA ewes, the Glucose Infusion Rate (GIR) was constant at approximately 5.8 mg glucose/kg/min during the last 40 minutes of the hyperglycaemic clamp and the Mean Plasma Insulin Increment (MPII) was only significantly (p < 0.001) greater in NPNL ewes. Following the clamp, NEFA concentrations were reduced by approximately 60% of pre-clamp levels in all groups, though a blunted and suppressed insulin response was maintained in 105 and 135 dGA ewes.ConclusionsResults suggest that despite an acute suppression of circulating NEFA concentrations during pregnancy, the associated steroids and hormones of pregnancy and possibly NEFA metabolism, may act to maintain a reduced insulin output, thereby sparing glucose for non-insulin dependent placental uptake and ultimately, fetal requirements.

Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.

Both insulin resistance and beta-cell dysfunction play a role in the transition from normal glucose tolerance (NGT) to Type 2 diabetes (T2DM) through impaired glucose tolerance (IGT). The aim of the study was to define the level of glycaemia at which beta-cell dysfunction becomes evident in the context of existing insulin resistance. Insulin response (OGTT) and insulin sensitivity (euglycaemic insulin clamp) were evaluated in 388 subjects in the San Antonio Metabolism (SAM) study (138 NGT, 49 IGT and 201 T2DM). In all subjects the insulin secretion/insulin resistance index (DeltaI/DeltaG/IR) was calculated as the ratio of the increment in plasma insulin to the increment in plasma glucose during the OGTT divided by insulin resistance, as measured during the clamp. In lean NGTs with a 2-h plasma glucose concentration (2-h PG) between 5.6 and 6.6 and between 6.7 and 7.7 mmol/l, there was a progressive decline in DeltaI/DeltaG/IR compared with NGTs with a 2-h PG less than 5.6 mmol/l. There was a further decline in DeltaI/DeltaG/IR in IGTs with a 2-h PG between 7.8 and 9.3 and between 9.4 and 11.0 mmol/l, and in Type 2 diabetic patients with a 2-h PG greater than 11.1 mmol/l. Lean and obese subjects showed coincident patterns of relation of 2-h PG to DeltaI/DeltaG/IR. When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in "normal" glucose tolerant individuals.

Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction.

The goal of this study was to identify the glycaemic status and investigate the roles of peripheral insulin resistance (IR) and pancreatic -cell dysfunction in the pathogenesis of cystic fibrosis-related diabetes (CFRD) in adult cystic fibrosis (CF) patients with no previous history of glycaemic disturbances. The glucose tolerance status of 68 CF patients was determined using 2-h oral glucose tolerance tests (OGTTs). Peripheral IR was measured using the homeostasis model assessment for insulin resistance (HOMA-IR) in the CF group and 46 normal healthy control subjects. Pancreatic -cell function, calculated as the ratio between the 30-min increment in plasma insulin and the corresponding 30-min post-OGTT plasma glucose concentration, was also measured in a subset of 30 CF patients and 16 normal healthy controls. Extended 180-min OGTTs, with frequent plasma glucose and insulin sampling, were also undertaken in 24 CF patients and eight normal healthy controls to determine glucose-induced insulin response. Of the 68 CF patients studied, 41, 18 and nine were found to have normal, impaired and diabetic glucose tolerances, respectively. The mean HOMA-IR values (mU/mmol) in the CF patients, as a whole, were not significantly different compared with the normal healthy controls (CF 2.2 +/- 1.1 vs. control 1.8 +/- 0.9; NS). Within the CF group, glycaemic status had no impact on HOMA-IR (mU/mmol): 2.2 +/- 1.2 (normal glucose tolerance); 2.0 +/- 1.0 (impaired glucose tolerance); and 2.3 +/- 1.1 (diabetic glucose tolerance). -cell function (mU/mmol) was not only significantly lower in the CF group (CF 1.65 +/- 1.8; P < 0.001) but also in the CF group with normal glucose tolerance (2.25 +/- 2.10; P < 0.01) compared with healthy control (4.98 +/- 2.38). Mean plasma glucose concentrations were generally higher and mean plasma insulin concentrations lower in the CF group as a whole when compared with normal healthy controls. Within the CF group, there was a progressive decline in glucose-induced insulin release with worsening glycaemic status. A lack of difference in peripheral IR, measured using HOMA-IR, in the CF group and healthy controls or within the CF group with differing glycaemic status suggests that IR does not have a significant role in the pathogenesis of CFRD. Pancreatic -cell function, already subnormal in CF patients with OGTT-defined normal glucose tolerance status, deteriorated further with worsening glycaemic status. This suggests that insulinopenia plays a prominent role in the pathogenesis of glucose intolerance and subsequent development of CFRD.