Insulin Secretion In Subjects Research Articles

Sex-differences in insulin sensitivity and insulin secretion in subjects with impaired fasting glucose and impaired glucose tolerance

AimsTo assess sex-related differences in whole-body insulin sensitivity and insulin secretion in a group of Caucasian subjects with varying degrees of glucose tolerance. MethodsSex-related differences in insulin sensitivity using the hyperinsulinemic–euglycemic clamp technique and insulin secretion using validated indexes obtained during an oral glucose tolerance test were examined among 570 non-diabetic offspring individuals having only one parent with type 2 diabetes. Participants were classified as having with NGT, isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG/IGT. ResultsIsolated IFG, isolated IGT, and combined IFG/IGT women exhibited greater relative differences in BMI, waist circumference, and insulin-stimulated glucose disposal than their male counterparts. Formal tests for glucose tolerance status × sex interaction were statistically significant for BMI (P = 0.05) waist circumference (P = 0.04), and insulin-stimulated glucose disposal (P = 0.01) suggesting a sex-specific association. By contrast, tests for glucose tolerance status × sex interaction regarding both insulinogenic and disposition indexes were not significant. ConclusionsThis study suggests that deterioration of glucose homeostasis in women is associated with a greater fat accumulation and worsening in insulin sensitivity as compared with men.

Impact of oral anticholinergic on insulin response to oral glucose load in patients with impaired glucose tolerance.

Background:Preliminary data indicates there is a cholinergic basis to insulin secretion.Aims & Objective:To investigate the impact of oral anticholinergics on insulin secretion in subjects with impaired glucose tolerance (IGT), in comparison with volunteers having normal glucose tolerance (NGT). Material & Methods: This prospective observational study recruited 10 IGT and 10 NGT subjects. An oral glucose tolerance test (OGTT) was conducted twice in the absence and presence of hyoscine butyl-bromide (HBB). The plasma glucose (PG) and insulin levels were serially estimated at 30-min increments for 2 h after the OGTT. Early (ΔI30/ΔPG30) & late (insulin/PGAUC 60-120) phase insulin activity were assessed subsequently.Results:The study constituted of 10 IGT (4M/6F, BMI: 28.80 ± 2.30) and 10 NGT (5M/5F, BMI: 23.00 ± 0.80) subjects. In the NGT group, the pre-HBB mean glucose levels (0-120 min) were comparable with those recorded after HBB intake. However, after HBBB, the mean insulin levels decreased significantly at t = 90 and 120min, confirmed by attenuated late phase insulin activity in IGT (P = 0.023) & NGT (P = 0.006) group. On the other hand, in the IGT group, however, HBB did not impact on the mean PG and insulin levels (0-120 min).Conclusions:Our study findings indicate that insulin secretion is influenced by cholinergic system and that oral anticholinergics may attenuate the late phase insulin activity in varying degrees of glycemic status.

1834-P: Pancreatic Fat Associates with Impaired Insulin Secretion in Genetically Predisposed Individuals

Background: Pancreatic fat (PF) related beta-cell failure might play a role in the pathophysiology of type 2 diabetes (T2D). We hypothesized that the effect of PF on beta-cell function can be modeled as a gene x environment interaction. To this end, we investigated the association of PF with insulin secretion in subjects with different genetic predisposition for T2D. Methods: A genome-wide polygenic risk score (gwPRS) was computed combining summary statistics from a genome-wide association study with ∼900.000 participants and 480.000 genetic variants in our cohort. The interaction of MRI-measured PF with gwPRS was investigated in 376 nondiabetic participants. Results: PF interacted with gwPRS on insulin secretion after adjustment for confounders (p=0.001). In participants with low gwPRS, PF associated positively with insulin secretion. In participants with high gwPRS, there was a negative association with insulin secretion. Discussion: PF is a pathophysiologic factor potentially contributing to both primary insulin hypersecretion and impairment of insulin secretion, dependent on genetic predisposition. Disclosure B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi. J. Machann: None. F. Schick: None. S. Ullrich: Advisory Panel; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H. Haering: None. A. Fritsche: None. R. Wagner: Other Relationship; Self; Lilly Diabetes, Novo Nordisk A/S. Funding German Federal Ministry of Education and Research

Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome

Objective Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome. Design In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test. Results There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010). Conclusions The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Insulin Secretion in Subjects With Type 2 Diabetes and Vitamin D Deficiency: A Randomized Controlled Trial.

In observational studies, low vitamin D levels are associated with type 2 diabetes (T2D), impaired glucose metabolism, insulin sensitivity, and insulin secretion. We evaluated the efficacy of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with T2D and low vitamin D (25-hydroxyvitamin D [25(OH)D] <50 nmol/L). Sixty-two men and women with T2D and vitamin D deficiency participated in a 6-month randomized, double-blind, placebo-controlled trial. Participants received a single dose of 400,000 IU oral vitamin D3 or placebo, and the vitamin D group received an additional 200,000 IU D3 if serum 25(OH)D was <100 nmol/L after 4 weeks. Primary end points were total Rd by euglycemic clamp with assessment of endogenous glucose production and first-phase insulin secretion by intravenous glucose tolerance test. In the vitamin D group, the mean ± SD baseline serum 25(OH)D of 38.0 ± 12.6 nmol/L increased to 96.9 ± 18.3 nmol/L after 4 weeks, 73.2 ± 13.7 nmol/L after 3 months, and 53.7 ± 9.2 nmol/L after 6 months. The total exposure to 25(OH)D during 6 months (area under the curve) was 1,870 ± 192 and 1,090 ± 377 nmol/L per week in the vitamin D and placebo groups, respectively (P < 0.001). Insulin sensitivity, endogenous glucose production, and glycemic control did not differ between or within groups after treatment (P = 0.52). First-phase insulin secretion did not change significantly after treatment (P = 0.10). Replenishment with a large dose of vitamin D3 to patients with T2D and vitamin D deficiency did not change insulin sensitivity or insulin secretion. These findings do not support such use of therapeutic vitamin D3 supplementation to improve glucose homeostasis in patients with T2D.

Insulin Sensitivity or Resistance in Type 2 Diabetes Mellitus with Obesity

Type 2 diabetes mellitus, a state of hyperglycemia associated with beta cell dysfunction or insulin action on target cells. This state is often mediated or sustained by obesity linked inflammatrory cytokines. Tumor necrosis factor-alpha (TNF-α), most important inflammatory cytokine plays critical role in the pathogenesis of type 2 diabetes mellitus as evidenced from higher circulating levels of TNF-α in type 2 diabetes mellitus compared to controls and its negative influence on insulin secretion and insulin sensitivity in type 2 diabetes mellitus. Positive association of TNF-α with insulin secretion in subjects with impaired glucose regulation indicates its causal relationship betacell dysfunction, insulin resistance or sensitivity. In obese subjects with type 2 diabetes mellitus, we observed stronger and graded relationship between TNF-α and obesity.

Assessment of beta-cell function and insulin secretion in subjects that underwent renal transplantation.

In this study we aimed to assess the performance of various indices of beta-cell function derived from oral glucose tolerance test (OGTT) in subjects that underwent renal transplantation. Impaired insulin secretion seems in fact central for development of new onset diabetes after transplantation, but its assessment has not been systematically evaluated. Twenty subjects underwent a 75 g 2h-OGTT for measurement of glucose, insulin, C-peptide. OGTT indices of beta-cell function were either derived by mathematical modeling (yielding the reference index: glucose sensitivity) or were empirical: insulinogenic index (IGI), IGI derived indices, whole shape C-peptide (WHOSH_CP). Indices of beta cell function, showed significant correlation with glucose sensitivity (R(2)=0.40-0.86, all P<;0.003). The majority of beta-cell function indices provided comparable results also when subjects were divided into subgroups according to sex, age, body mass index, mean glycemia. In conclusion, in transplanted subjects OGTT empirical indices are typically acceptable for the estimation of beta-cell function.

Effect of vitamin D supplementation on insulin kinetics and cardiovascular risk factors in polycystic ovarian syndrome: a pilot study.

To assess the effect of vitamin D supplementation on parameters of insulin sensitivity/resistance (IS/IR) and insulin secretion in subjects with polycystic ovarian syndrome (PCOS). A prospective double-blind randomized control trial was conducted to assess the effect of vitamin D on insulin kinetics in women with PCOS. The trial was conducted in a tertiary care research hospital. A total of 36 subjects with PCOS, aged 18–35 years, were included in this study. Vitamin D3 4000 IU/day versus placebo was given once a month for 6 months and both groups received metformin. IS (by whole-body IS index or Matsuda index), IR (by homeostasis model assessment IR (HOMA-IR)), and insulin secretion (by insulinogenic index; II30) were the main outcome measures. Secondary outcome included blood pressure (BP), lipid profile, disposition index (DI), and vascular stiffness. Out of 36 subjects who consented, 32 completed the study. Subjects were randomized into two groups: group A (n=15; metformin and vitamin D 4000 IU/day) or group B (n=17; metformin and placebo). Oral glucose tolerance tests with 75 g glucose were carried out at baseline and 6 months after supplementation. Hypovitaminosis D was observed in 93.8% of all subjects with mean serum 25 hydroxy vitamin D level of 7.30±4.45 ng/ml. After 6 months of vitamin D supplementation, there was no significant difference in any of the parameters of IS/IR (area under curve (AUC)–glucose, AUC–insulin, insulin:glucose ratio, HOMA-IR, Matsuda index, insulinogenic index, and DI), II30, and cardiovascular risk factors between the two groups. Supplementation of vitamin D, at a dose of 4000 IU/day for 6 months, did not have any significant effect on parameters of IS/IR and insulin secretion in subjects with PCOS.

The relationship between serum calcium level and early-phase insulin secretion in normoglycemic and pre-diabetic individuals.

Type 2 diabetes mellitus (T2DM) is linked to altered calcium metabolism. However, little is known about the relationship between serum calcium levels and early-phase insulin secretion in subjects with normoglycemic tolerance (NGT) or prediabetes (preDM). In this gender-separated cross-sectional study, 352 subjects with NGT (215 men and 137 women; age: 48.8±9.1 years and 51.6±6.7 years, respectively) and 316 subjects with preDM (231 men and 85 women; age: 52.5±8.6 years and 54.2±8.0 years, respectively) were examined. Following a 75-g oral glucose tolerance test, early-phase insulin secretion was estimated using the insulinogenic index (IGI) [ΔInsulin(30-0 min)/ΔGlucose(30-0 min)]. Simple linear regression analysis showed that IGI was positively correlated with serum calcium and albumin-adjusted calcium levels in men with NGT and preDM. However, IGI was not correlated with calcium levels in women with NGT and preDM. Multivariate linear regression analysis of men with NGT revealed that the albumin-adjusted calcium level was the major predictor of IGI, responsible for 5.1% of its variation (P=0.003). In addition, in men with preDM, the albumin-adjusted calcium level was one of the predictors of IGI, responsible for 3.8% of its variation (P=0.004). These associations were independent of age, BMI, and HbA1c. In non-diabetic Japanese men, serum calcium levels significantly correlate with early-phase insulin secretion. Serum calcium levels may be an independent predictor of β-cell function in men.

Abstract 017: Spironolactone Improves Insulin Secretion In Metabolic Syndrome Subjects

Renin-angiotensin-aldosterone system blockade reduces the incidence of type 2 diabetes in clinical trials. We previously demonstrated that aldosterone impairs insulin secretion via a direct beta-cell effect in mice. To test the hypothesis that aldosterone and the mineralocorticoid receptor contribute to impaired insulin secretion in humans, we enrolled subjects with metabolic syndrome treated with hydrochlorothiazide (HCTZ) 12.5 mg daily for 4 weeks (baseline) followed by either Spironolactone 25 mg daily (SPL, n=16) versus Aliskiren 150 mg daily (ALI, n=19) for 4 weeks. We assessed insulin secretion and sensitivity using hyperglycemic clamps during sodium controlled diet (160 mmol Na). During HCTZ alone, plasma aldosterone correlated inversely with the initial insulin response and disposition index (Figure A), but not with insulin sensitivity index. Plasma aldosterone decreased during aliskiren (-1.5±0.78 ng/dL) and increased during spironolactone treatment (+4.0±0.8 ng/dL; p&lt;0.001 between treatment). Blood pressure, serum potassium, and insulin sensitivity index were unchanged. The acute insulin response increased compared to baseline during SPL compared to ALI (+11.6±7.9 vs -10.7±7.7 μU/mL; p=0.048), whereas insulin sensitivity index was unchanged. We conclude that aldosterone is inversely associated with the initial phase insulin secretory response, the earliest detectable change in impaired glucose tolerance. Treatment with spironolactone could improve glucose homeostasis by restoring insulin secretion in subjects with metabolic syndrome.

Impact of the Adipokine Adiponectin and the Hepatokine Fetuin-A on the Development of Type 2 Diabetes: Prospective Cohort- and Cross-Sectional Phenotyping Studies

BackgroundAmong adipokines and hepatokines, adiponectin and fetuin-A were consistently found to predict the incidence of type 2 diabetes, both by regulating insulin sensitivity.ObjectiveTo determine to what extent circulating adiponectin and fetuin-A are independently associated with incident type 2 diabetes in humans, and the major mechanisms involved.MethodsRelationships with incident diabetes were tested in two cohort studies: within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (628 cases) and the Nurses' Health Study (NHS; 470 cases). Relationships with body fat compartments, insulin sensitivity and insulin secretion were studied in the Tübingen Lifestyle Intervention Program (TULIP; N = 358).ResultsCirculating adiponectin and fetuin-A, independently of several confounders and of each other, associated with risk of diabetes in EPIC-Potsdam (RR for 1 SD: adiponectin: 0.45 [95% CI 0.37–0.54], fetuin-A: 1.18 [1.05–1.32]) and the NHS (0.51 [0.42–0.62], 1.35 [1.16–1.58]). Obesity measures considerably attenuated the association of adiponectin, but not of fetuin-A. Subjects with low adiponectin and concomitantly high fetuin-A had the highest risk. Whereas both proteins were independently (both p<1.8×10−7) associated with insulin sensitivity, circulating fetuin-A (r = −0.37, p = 0.0004), but not adiponectin, associated with insulin secretion in subjects with impaired glucose tolerance.ConclusionsWe provide novel information that adiponectin and fetuin-A independently of each other associate with the diabetes risk. Furthermore, we suggest that they are involved in the development of type 2 diabetes via different mechanisms, possibly by mediating effects of their source tissues, expanded adipose tissue and nonalcoholic fatty liver.

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

Lipoproteins and β-Cell Functions: From Basic to Clinical Data.

L-Arginine enriched biscuits improve endothelial function and glucose metabolism: A pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome

ObjectiveThe aim of this study was to evaluate the effects of a new l-arginine-enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition. Materials/MethodsThe project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of l-arginine-enriched biscuits that contained 6.6gl-arginine, 21.9g carbohydrates, 3.6g protein, 7.5g fat and 4.3g dietary fiber compared with placebo biscuits and 6.6g powdered l-arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6g of l-arginine-enriched biscuits or placebo biscuits in a 1600kcal diet. Each study period lasted 2weeks with a 2-week washout in between. Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period. ResultsIn the first study, the groups that received the l-arginine-enriched biscuits and the powdered l-arginine had similarly increased l-arginine, NOx and cGMP levels and post-ischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the l-arginine-enriched biscuit recipient group displayed increased l-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group. Conclusionsl-Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS.

Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose

Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60-120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.

Genetic variation within the NR1H2 gene encoding liver X receptor β associates with insulin secretion in subjects at increased risk for type 2 diabetes

The liver X receptors (LXRs)-α and -β play a crucial role in control of insulin production and secretion in pancreatic β-cells. We hypothesized that common variants in the NR1H2 and NR1H3 genes, encoding LXR-β and -α, respectively, may alter pancreatic β-cell function. One thousand five hundred seventy-four subjects of European ancestry with elevated risk for type 2 diabetes were genotyped for the two NR1H2 single nucleotide polymorphisms (SNPs) rs2248949 and rs1405655 and for the four NR1H3 SNPs rs11039149, rs3758673, rs12221497 and rs2279238, and association studies with metabolic traits were performed. Metabolic characterization comprised an oral glucose tolerance test (OGTT) in all participants and, in addition, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test (IVGTT) in subsets. One hundred per cent of common genetic variation (minor allele frequency ≥1%) within the NR1H2 and NR1H3 loci (D' = 1.0; r² ≥ 0.8) were covered by the six chosen tagging SNPs. NR1H2 rs2248949 was nominally associated with OGTT-derived first-phase insulin secretion and proinsulin conversion to insulin and significantly associated with the AUC of insulin levels during the IVGTT (p = 0.007) after adjustment for age, gender, BMI and insulin sensitivity in the dominant model, with the minor allele conferring reduced pancreatic β-cell function to the carriers. In subjects of European ancestry at increased risk for type 2 diabetes, common variation within the NR1H2 gene impaired insulin secretion, which may facilitate the development of type 2 diabetes.

Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: a nuclear magnetic resonance study

The pathogenesis of type 2 diabetes is characterized by insulin resistance and beta-cell dysfunction. Pancreatic fat load may add to the development of beta-cell dysfunction. The aim was to thoroughly quantify the fat content of pancreas sections (caput, corpus, and cauda) and to compare the impact of pancreatic, intrahepatic, and visceral fat on insulin secretion in humans. Fifty-one subjects were subjected to an oral glucose tolerance test (OGTT) with glucose, insulin, and C-peptide measurements [28 subjects displayed normal glucose tolerance, 23 impaired fasting glycemia (IFG)] and/or impaired glucose tolerance (IGT)], and also to whole-body magnetic resonance imaging (MRI), pancreas MRI, and liver magnetic resonance spectroscopy (MRS). After adjustment for gender and age, the mean pancreatic fat content was positively associated with body mass index (BMI), visceral adipose tissue (VAT), and waist circumference (all p < or = 0.0013). The mean pancreatic fat content was negatively associated with OGTT-based measures of insulin secretion (all p < or = 0.03). Analysis of the subgroups of glucose tolerance showed that this was restricted to subjects with IGT and/or IFG. Visceral fat also represented a determinant of beta-cell function in individuals with IGT and/or IFG (all p < or = 0.02), whereas intrahepatic fat did not. In a stepwise multivariate regression analysis, pancreatic fat turned out to be a stronger determinant of impaired insulin secretion than visceral fat. Pancreatic fat is negatively associated with insulin secretion in subjects with IGT/IFG and, therefore, might represent an additional pathogenetic factor leading to beta-cell dysfunction.

The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance.

To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.

Decreased Insulin Secretion and Insulin Sensitivity Are Associated With Liver Function in Subjects With Fasting Glucose Between 100 and 109 mg/dL in Taiwanese Population

In 2003, the American Diabetes Association recommended that the lower limit for the diagnosis of impaired fasting glucose (IFG) should be reduced from 110 to 100 mg/dL in the analysis of the associated risk factors of IFG. It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. A primary aim was to investigate the relationship between liver enzyme and insulin resistance (IR) in IFG group. The secondary aim was to investigate IR and beta-cell function assessed by homeostasis model assessment (HOMA-IR and HOMA-%B, respectively) in subjects with fasting plasma glucose (FPG) between 100 and 109 mg/dL. We enrolled 284 subjects whose medical history and physical examination required tests to screen for metabolic abnormalities. In addition, we also excluded all factors affecting glucose or insulin metabolism. According to the FPG level, they were divided into the following groups: group A, FPG < 100 mg/dL; group B, FPG = 100 to 109 mg/dL; group C, FPG = 110 to 125 mg/dL. Group B as compared with group A had significant increase of HOMA-IR and decrease of HOMA-%B. Among the whole population, the fasting insulin level, the fasting glucose, HbA1c, HOMA-IR, alanine aminotransferase, gamma-glutamyltranspeptidase, aspartate aminotransferase, and the diastolic blood pressure all increased significantly as the glycemic status progressed, whereas HOMA-%B levels decreased significantly as the glycemic status progressed. The lipid profile, alkaline phosphatase, and systolic blood pressure did not differ significantly among 3 different glycemic classifications. Study results indicate that, first, there was a significant decrease of insulin sensitivity and insulin secretion in subjects with fasting glucose from 100 to 109 mg/dL compared with subjects with normal fasting glucose. Second, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltranspeptidase were associated with IR as the glycemic status progressed in the IFG group.

Insulin Secretion and Insulin Sensitivity in Relation to Fasting Glucose in Healthy Subjects

This study evaluated insulin secretion and insulin sensitivity in healthy subjects with normal fasting glucose. A total of 148 healthy women (aged 53-70 years) underwent a glucose-dependent arginine stimulation test and a 2-h euglycemic-hyperinsulinemic clamp. In the arginine test, arginine (5 g) was injected intravenously under baseline (fasting) conditions and after raising the glucose levels to 15 and >28 mmol/l. From this test, the acute insulin response (AIR) to arginine during the three glucose levels (AIR1, AIR2, and AIR3) were estimated. The subjects were divided into quartiles of fasting glucose (n = 37 in each group [range <4.32; 4.33-4.84; 4.85-5.22; and 5.23-6.1 mmol/l, respectively). The results show that 1) AIR1 was higher in subjects in the two highest quartiles (P = 0.004), 2) AIR3 was higher in the quartile with the highest fasting glucose (P = 0.012), and 3) insulin sensitivity was reduced in subjects in the highest quartile (P = 0.026) compared with the lower quartiles. The results also show, in contrast, that AIR2 did not show a similar trend to be increased at higher fasting glucose. It is concluded that 1) raised fasting glucose (albeit still within normal values) augments baseline and maximal arginine-induced insulin secretion in healthy subjects, and 2) this is associated with reduced insulin sensitivity. This suggests that high, but still normal, fasting glucose may contribute to the augmented insulin secretion in subjects with low insulin sensitivity.

Interaction between cholesterol and glucose metabolism during dietary carbohydrate modification in subjects with the metabolic syndrome

Carbohydrate modification based on rye bread and pasta enhances early insulin secretion in subjects with the metabolic syndrome. Because the actions of insulin and cholesterol metabolism are interrelated, the question is raised of whether it is possible to alter cholesterol metabolism by means of dietary carbohydrate modification. We investigated the 12-wk effects of dietary carbohydrate modification on cholesterol synthesis and absorption by measuring the ratios of surrogate markers of precursor (cholestenol, desmosterol, and lathosterol) and absorption (cholestanol and plant sterols) sterols to cholesterol and their association to glucose metabolism in 74 subjects with the metabolic syndrome. The subjects were randomly assigned to diets with rye bread and pasta (RPa) or oat, wheat bread, and potato (OWPo) as the main carbohydrate source (34% and 37% of energy intake, respectively). During the study, serum cholesterol concentrations remained unchanged. Cholesterol synthesis was lower (6-10% for cholestenol and lathosterol; P < 0.05) and absorption higher (9%; P < 0.05 for sitosterol) with the OWPo diet than at baseline. With the RPa diet, cholesterol absorption was lower and synthesis higher than with the OWPo diet. The increment in the glucose area under the curve with the RPa diet was positively related to baseline cholesterol synthesis (eg, lathosterol; r = 0.480, P < 0.05) and negatively to absorption (for cholestanol; r = -0.520, P < 0.05). In the combined group, the changes in the cholestanol ratio and the insulinogenic index were interrelated (r = -0.464, P < 0.001). Carbohydrate modifications had dissimilar effects on cholesterol metabolism. Consumption of RPa, as compared with OWPo, may be clinically more favorable because it seems to inhibit the absorption of cholesterol, a factor crucial in the development of arterial atherosclerosis.