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Background/objectives: Despite considerable literature supporting the potential health benefits of reducing postprandial glucose (PPG), and insulin (PPI) exposures, the size of a clinically relevant reduction is currently unknown. We performed a systematic review and meta-analysis to quantify effects of alpha-glucosidase-inhibiting (AGI) drugs on acute PPG and PPI responses. Methods: We searched EMBASE and MEDLINE until March 13, 2018 for controlled studies using AGI drugs together with a standardized carbohydrate load or mixed meal. The mean incremental PPG and PPI levels were calculated as outcomes. Meta-analyses, stratified by diabetes state, were performed by using random effects models. Results: The 66 included publications comprised 127 drug-control comparisons for PPG, and 106 for PPI, mostly testing acarbose or miglitol. The absolute effects on PPG were larger among individuals with diabetes (−1.5 mmol/l mean PPG [95% CI −1.9, −1.1] by acarbose, and −1.6 [−1.9, −1.4] by miglitol) as compared to individuals without diabetes (−0.4 [95% CI −0.5, −0.3] by acarbose, and −0.6 [−0.8, −0.4] by miglitol). Relative reductions in PPG by both drugs were similar for diabetic and non-diabetic individuals (43−54%). Acarbose and miglitol also significantly reduced mean PPI, with absolute and relative reductions being largest among individuals without diabetes. Conclusions: The present meta-analyses provide quantitative estimates of reductions of PPG and PPI responses by AGI drugs in diabetes and non-diabetic individuals. These data can serve as benchmarks for clinically relevant reductions in PPG and PPI via drug or diet and lifestyle interventions. [ABSTRACT FROM AUTHOR]

Aim: To examine the hypothesis that, based on their glucose curves during a seven‐point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. Methods: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI‐DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven‐point oral glucose tolerance test at baseline and follow‐up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. Results: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1–4. Participants in Subgroups 2–4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13–0.58), Subgroup 3 (β = 0.30; 95% CI 0.10–0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04–0.32), compared to Subgroup 1. The same was observed for C‐peptide and insulin. Five subgroups were identified at follow‐up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. Conclusions: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified. [ABSTRACT FROM AUTHOR]

We conducted the first prospective observational study in which we examined the association between incretin responses to an oral glucose tolerance test (OGTT) and mixed meal test (MMT) at baseline and changes in fasting glucose levels 7 years later, in individuals who were non-diabetic at baseline. We used data from the Hoorn Meal Study; a population-based cohort study among 121 subjects, aged 61.0±6.7y. GIP and GLP-1 responses were determined at baseline and expressed as total and incremental area under the curve (tAUC and iAUC). The association between incretin response at baseline and changes in fasting glucose levels was assessed using linear regression. The average change in glucose over 7 years was 0.43 ± 0.5 mmol/l. For GIP, no significant associations were observed with changes in fasting glucose levels. In contrast, participants within the middle and highest tertile of GLP-1 iAUC responses to OGTT had significantly smaller increases (actually decreases) in fasting glucose levels; -0.28 (95% confidence interval: -0.54;-0.01) mmol/l and -0.39 (-0.67;-0.10) mmol/l, respectively, compared to those in the lowest tertile. The same trend was observed for tAUC GLP-1 following OGTT (highest tertile: -0.32 (0.61;-0.04) mmol/l as compared to the lowest tertile). No significant associations were observed for GLP-1 responses following MMT. In conclusion, within our non-diabetic population-based cohort, a low GLP-1 response to OGTT was associated with a steeper increase in fasting glucose levels during 7 years of follow-up. This suggests that a reduced GLP-1 response precedes glucose deterioration and may play a role in the etiology of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. Methods The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System ( n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c. Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time. Results Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. Conclusions Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, e211-e216 (2012) Abstract Aim Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting β-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of β-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. Methods A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance ( n = 261) and impaired glucose tolerance ( n = 188). From 2-h hyperglycaemic clamps, first- and second-phase glucose-stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9β A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and β-cell function parameters were assessed. Results In women, but not in men, the N363S polymorphism was associated with reduced disposition index ( P = 1.06 10−4). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion ( P = 0.011) and disposition index ( P = 0.003). The other single-nucleotide polymorphisms were not associated with β-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. Conclusion The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of β-cell function in women, but not in men. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk Callele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism. [ABSTRACT FROM AUTHOR]

The article provides information on a study which examined the longitudinal patterns of antidiabetic drug modifications after initiation of oral antidiabetic therapy among type 2 diabetics in the Netherlands. Calculation of the theoretical duration of use for each prescription is discussed. The difference between patients initiating treatment with metformin or sulfonylureas is highlighted. The most frequent first additions received include thaxolidinediones and insulin.

OBJECTIVE--Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of β-cell function. RESEARCH DESIGN AND METHODS--For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/ CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B. RESULTS--Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 x 10-3). The THADA gene variant was associated with lower β-cell response to GLP-1 and arginine (both P < 1.6 x 10-3), suggesting lower β-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with β-cell function. CONCLUSIONS--Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of β-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic β-cells. Diabetes 59: 293-301, 2010 [ABSTRACT FROM AUTHOR]

The objective of this investigation was to determine the relation between baseline glucose, insulin, adiponectin, and leptin levels and subsequent 6-year weight and waist change in older men and women without diabetes in a prospective cohort study. Participants were 1,198 Dutch men and women without diabetes who were aged 50–77 years when baseline metabolic and anthropometric measurements were evaluated (1989–1991). Approximately 6 years later, body weight and waist circumference were re-measured at a follow-up examination (1996–1998). Metabolic variables (fasting plasma glucose, 2-h postchallenge plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and leptin) were evaluated as predictors of changes in weight and waist circumference. Postchallenge plasma glucose (mmol/l) significantly predicted less gain in both weight and waist circumference (β = −0.28 kg, s.e. = 0.11; β = −0.31 cm, s.e. = 0.14, respectively) during follow-up. Leptin (µg/l) significantly predicted greater increases in weight (β = 0.29 kg, s.e. = 0.07) and waist (β = 0.16 cm, s.e. = 0.08) among men and in waist among women (β = 0.06 cm, s.e. = 0.02). Fasting plasma glucose (mmol/l) predicted an increase in waist among women (β = 1.59 cm, s.e. = 0.63), but not in men (β = −0.74 cm, s.e. = 0.55). Adiponectin and insulin did not predict weight or waist change. The authors conclude that lower postchallenge plasma glucose and higher fasting leptin levels significantly predicted long-term increases in weight and waist circumference. In contrast, measures of insulin resistance and adiponectin were not associated with weight change in this cohort of older persons without diabetes.Obesity (2009) 17 8, 1609–1614. doi:10.1038/oby.2008.666 [ABSTRACT FROM AUTHOR]

Background/Objective:Early insulin secretion following a meal is representative for normal physiology and may depend on meal composition. To compare the effects of a fat-rich and a carbohydrate-rich mixed meal on insulinogenic index as a measure of early insulin secretion in normoglycemic women (NGM) and in women with type 2 diabetes mellitus (DM2), and to assess the relationship of anthropometric and metabolic factors with insulinogenic index.Subjects/Methods:Postmenopausal women, 76 with NGM and 64 with DM2, received a fat-rich meal and a carbohydrate-rich meal on separate occasions. Early insulin response was estimated as insulinogenic index (△insulin0–30 min/△glucose0−30 min) for each meal. Associations of fasting and postprandial triglycerides, body mass index, waist and hip circumference and alanine aminotransferase with insulinogenic indices were determined.Results:Women with NGM present with higher insulinogenic index than women with DM2. The insulinogenic index following the fat-rich meal (△I30/△G30 (fat)) was higher than the index following the carbohydrate-rich meal (△I30/△G30 (CH)) (P<0.05 in women with DM2, and not significant in women with NGM). In women with DM2, homeostasis model assessment for insulin resistance was positively associated with △I30/△G30 (CH). In women with NGM, waist circumference was independently and inversely associated with △I30/△G30 (fat) and with △I30/△G30 (CH); hip circumference was positively associated with △I30/△G30 (fat).Conclusions:The insulinogenic index following the fat-rich meal was higher than following the isocaloric carbohydrate-rich meal, which might favorably affect postprandial glucose excursions, especially in women with DM2. The association between a larger waist circumference and a lower meal-induced insulinogenic index in women with NGM requires further mechanistic studies.European Journal of Clinical Nutrition (2009) 63, 398–404; doi:10.1038/sj.ejcn.1602953; published online 7 November 2007 [ABSTRACT FROM AUTHOR]

The short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) protein is involved in the penultimate step of mitochondrial fatty acid oxidation. Previously, it has been shown that mutations in the corresponding gene (HADHSC) are associated with hyperinsulinism in infancy. The presumed function of the SCHAD enzyme in glucose-stimulated insulin secretion led us to the hypothesis that common variants in HADHSC on chromosome 4q22-26 might be associated with development of type 2 diabetes. In this study, we have performed a large-scale association study in four different cohorts from the Netherlands and Denmark (n = 7,365). Direct sequencing of HADHSC cDNA and databank analysis identified four tagging single nucleotide polymorphisms (SNPs) including one missense variant (P86L). Neither the SNPs nor haplotypes investigated were associated with the disease, enzyme function, or any relevant quantitative measure (all P > 0.1). The present study provides no evidence that the specific HADHSC variants or haplotypes examined do influence susceptibility to develop type 2 diabetes. We conclude that it is unlikely that variation in HADHSC plays a major role in the pathogenesis of type 2 diabetes in the examined cohorts. Diabetes 55:3193-3196, 2006 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS -- Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and β-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS -- Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS -- Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD. [ABSTRACT FROM AUTHOR]

Aims/hypotheses. Insulin resistance is thought to be a key predictor for the development of Type 2 diabetes mellitus and cardiovascular disease (CVD), a leading cause of morbidity and premature mortality in Europe. Insulin resistance is influenced by both genetic and lifestyle factors (e.g. obesity and physical inactivity). The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is using the infrastructure of an extended European collaborative research group to study insulin resistance and CVD risk in 1500 healthy people aged 30 to 60 years from 20 centres in 13 countries. Methods. Baseline measurements of glucose tolerance and insulin sensitivity are made by the oral glucose tolerance test and the euglycaemic insulin clamp, respectively; carotid artery intima-medial thickness (by ultrasound), ankle/brachial pressure index and electrocardiography will enable evaluation of subclinical CVD at baseline and at follow-up. Classic CVD risk factors, as well as socioeconomic and lifestyle factors will be recorded at baseline; samples for measurement of biochemical and genetic markers will be collected and stored for future analyses. Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis as measured by carotid artery intima-media thickness. Development of Type 2 diabetes, dyslipidaemia, obesity, hypertension and cardiovascular events are additional endpoints. Conclusions. This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

IGFs are important regulators of pancreatic beta-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI. [ABSTRACT FROM AUTHOR]

Objective: To compare steroids and their associations in men with type 1 diabetes and healthy control subjects.Research Design and Methods: We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample.Results: In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute.Conclusions: Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels. [ABSTRACT FROM AUTHOR]

An association between type 2 diabetes and genetic variation in the KIR6.2 gene has been reported in several populations. Based on in vitro studies with cell lines expressing the Glu(23)Lys (E23K) mutation, it was recently suggested that this mutation might result in altered insulin secretion. We have examined glucose-stimulated insulin secretion in relation to this KIR6.2 gene variant in two independent Dutch cohorts. Subjects with normal (n = 65) or impaired (n = 94) glucose tolerance underwent 3-h hyperglycemic clamps at 10 mmol/l glucose. We did not observe significant differences in first- or second-phase insulin secretion between carriers and noncarriers of the gene variant in either of the study populations (all P > 0.45). Furthermore, we found no evidence for a significant interaction with disease-associated gene variants in the sulfonylurea receptor (SUR1) gene. We conclude that the E23K mutation in the KIR6.2 gene is not associated with detectable alterations in glucose-stimulated insulin secretion in two independent populations from the Netherlands. [ABSTRACT FROM AUTHOR]

Associations between type 2 diabetes (and/or parameters contributing to glucose homeostasis) and genetic variation in the genes encoding insulin receptor substrate (IRS)-1 and -2 have been reported in several populations. Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. Subjects with normal (n = 64) or impaired (n = 94) glucose tolerance underwent 3-h hyperglycemic clamps at 10 mmol/l glucose. All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. We did not observe any significant difference in both first- and second-phase insulin secretion between carriers and noncarriers of both gene variants, nor was there evidence for an association with other diabetes-related parameters. We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at nt –3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion.¶Methods. Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were assessed by the hyperglycaemic clamp.¶Results. Frequencies of the exon 16 –3t allele in the normal and impaired glucose tolerant groups were 46 % and 44 % respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7 % respectively (p = NS). We observed an approximately 25 % reduced second-phase insulin secretion in carriers of the exon 16 –3t allele in both groups (p < 0.05). Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon 18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion or insulin sensitivity in our study groups.¶Conclusion/interpretation. The diabetes associated exon 16 –3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects. [Diabetologia (2000) 43: 515–519] [ABSTRACT FROM AUTHOR]

Investigates whether the length of the GAA trinucleotide repeat in the frataxin gene is associated with beta-cell function. Presence of short-length normal and intermediate-length alleles; Allele frequency for intermediate-length repeat; Effect of intermediate length repeat on insulin secretion.

The article presents the results of a study on the relationship of indices of insulin secretion in response to two challenges in persons with normal and abnormal glucose tolerances. Subjects were given an oral glucose tolerance test (OGTT) and a standardized mixed meal tolerance test (MTT). Insulin and glucose were determined at time 0, 30, 60, 90, 120 minutes post-challenge. The study concluded that there appears to be good correlation among indices of insulin secretion for the two challenges.

We studied whether parameters of beta cell function were similar during an oral glucose tolerance test (OGTT) and a -physiologically more relevant-mixed meal tolerance test (MTT) in different glucose tolerance groups. Individuals with normal glucose tolerance (NGT, n=150), intermediate hyperglycaemia (IH, n=19) and diabetes (DM, n=19) underwent an OGTT and an MTT, both containing 75g carbohydrates. The meal also contained 50g fat and 24g proteins. Plasma glucose, insulin and C-peptide were sampled before and 15, 30, 60, 90 and 120 minutes after OGTT and MTT. Insulin secretion rate (ISR) and beta cell function parameters were calculated from C-peptide using a mathematical model. These parameters included beta cell glucose sansitivity, i.e., the slope of the glucose concentration - ISR relationship and potentiation, which expresses a relative increase of ISR from the beginning to the end of the test. ANOVA and dependent t-tests with Bonferroni corrections were used to test for differences. Beta cell glucose sensitivity was higher during MTT than during OGTT in all groups (Table 1). Diabetic subjects had significantly lower beta cell glucose sensitivity than IH- and NGT-subjects. Potentiation was similar (NGT-or DM-subjects) or slightly higher (IH-subjects) during MTT. Beta cells were more sensitive to glucose (i.e. insulin secretion per glucose unit was higher) during a mixed meal load than during a glucose load while the ability to modulate this relationship (potentiation) was similar or slightly higher. Individuals with IH, unlike diabetic subjects, did not have lower beta cell sensitivity than NGT-individuals. We conclude that beta cell response is stronger after a mixed meal than after an OGTT with equal-carbohydrate quantity. [ABSTRACT FROM AUTHOR]

Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet. [ABSTRACT FROM AUTHOR]

Abstract: This study compared classical and model-based beta-cell responses during an oral glucose tolerance test (OGTT) and a meal tolerance test (MTT) in a population-based cohort. Individuals with normal glucose metabolism (NGM, n =161), impaired glucose metabolism (IGM, n =19) and type 2 diabetes mellitus (DM, n =20) underwent a 75g-OGTT and an MTT (75g carbohydrates, 50g fat, 24g proteins). Classical estimates of beta-cell function (insulinogenic index and the ratio of areas under insulin and glucose curves) were calculated. Mathematical modelling was used to determine beta-cell glucose sensitivity, rate sensitivity and potentiation. Insulin sensitivity was characterized by three surrogate estimates. Both classical and model-based estimates of beta-cell function were higher during MTT than during OGTT (P <0.05). Regarding the model-based parameters, especially beta-cell sensitivity was increased following MTT as compared with OGTT (P <0.05). Both during OGTT and MTT, across most parameters describing beta-cell function, the largest reduction in beta-cell response occurred between IGM and DM, while the largest reduction in insulin sensitivity occurred between NGM and IGM. We conclude that beta-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher beta-cell sensitivity during the meal. [Copyright &y& Elsevier]