Lower Early Insulin Response Research Articles

1343-P: A Comparison of C-Peptide and Glucose Responses between Children and Adolescents Who Progress to Type 1 Diabetes (T1D)

Type 1 diabetes is a heterogeneous disease with differences in β-cell dysfunction and rates of progression. We thus assessed whether there are differences in C-peptide and glucose responses during 2-hour oral (OGTTs) and intravenous (IVGTTs) glucose tolerance tests between children and adolescents at high risk for T1D. Data from the Diabetes Prevention Trial-type 1 (DPT-1) study participants who progressed to T1D was used for the analysis. We compared C-peptide and glucose responses between children (<10.0 years old; 7.1±1.9 years; n=125) and adolescents (10.0 years to <18.0 years old; 12.8±2.2 years; n=94). The risks for T1D were similar between the children and adolescents (mean 3-year T1D estimates from DPT-1 Risk Score: 63% and 56% respectively), as was the time to diagnosis (2.4±2.1 years vs. 2.5±2.2 years, respectively). Adolescents had higher OGTT derived AUC C-peptide levels (3.8±1.5 ng/ml vs. 1.9±1.4 ng/ml; p<0.001 with BMIZ adjustment), whereas their AUC glucose levels were similar to children (138.6±25.1 mg/dl vs. 139.6±22.8 mg/dl). The 0 to 30 minute C-peptide response from baseline OGTTs was significantly higher among adolescents compared to children (2.6±1.6 vs. 2.1±1.2, p=0.004 with BMIZ adjustment). However, C-peptide and glucose changes for each subsequent 30-minute OGTT interval were nearly identical between the children and adolescents. Similar to the 0 to 30 minute C-peptide response, the first-phase insulin response from baseline IVGTTs was higher in adolescents (114.1±74.0 µU/ml vs. 88.6±59.9 µU/ml; p<0.001 with BMIZ adjustment). In conclusion, the findings showed that despite a lower early insulin response in children, OGTT glucose levels were not higher. This suggests increased insulin sensitivity. The findings also showed that despite the lower early insulin response, the time to diagnosis did not differ. Other aspects of insulin responsiveness, and perhaps sensitivity, appear to also determine the progression rate to T1D. Disclosure H.M. Ismail: None. B.M. Nathan: None. J.P. Palmer: None. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research & Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. J.M. Sosenko: None. Funding National Institutes of Health

Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population

The relation between selenium status and risk of Type2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes. We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted. At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) μg/l. During 20years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio1.06; 95%CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized β -0.08; 95%CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of β-cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account. Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals.

Patterns of Insulin Concentration During the OGTT Predict the Risk of Type 2 Diabetes in Japanese Americans

OBJECTIVETo examine whether the patterns of insulin concentration during the oral glucose tolerance test (OGTT) predict type 2 diabetes.RESEARCH DESIGN AND METHODSWe followed 400 nondiabetic Japanese Americans for 10–11 years. Insulin concentrations at 30, 60, and 120 min during a 2-h 75-g OGTT at baseline were used to derive the following possible patterns of insulin: pattern 1 (30-min peak, higher insulin level at 60 than at 120 min), pattern 2 (30-min peak, lower or equal level at 60 vs. 120 min), pattern 3 (60-min peak); pattern 4 (120-min peak, lower level at 30 than at 60 min), and pattern 5 (120-min peak, equal or higher level at 30 vs. 60 min). Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Insulin secretion was estimated by the insulinogenic index (IGI) [Δinsulin/Δglucose (30–0 min)] and disposition index (IGI/HOMA-IR).RESULTSThere were 86 incident cases of type 2 diabetes. The cumulative incidence was 3.2, 9.8, 15.4, 47.8, and 37.5% for patterns 1, 2, 3, 4, and 5, respectively. Compared with pattern 1, patterns 4 and 5, characterized by a lasting late insulin response, were associated with significantly less insulin sensitivity as measured by the Matsuda index and lower early insulin response by the disposition index. The multiple-adjusted odds ratios of type 2 diabetes were 12.55 (95% CI 4.79–32.89) for pattern 4 and 8.34 (2.38–29.27) for pattern 5 compared with patterns 1 and 2. This association was independent of insulin secretion and sensitivity.CONCLUSIONSThe patterns of insulin concentration during an OGTT strongly predict the development of type 2 diabetes.

Evaluation of glycaemic status in young people with clinical insulin resistance; fasting glucose, fasting insulin or an oral glucose tolerance test?

It is important to identify young people with prediabetes for early intervention. However, it is unclear how to best screen overweight and obese young people for prediabetes. The objective of this study was to compare fasting indices with an oral glucose tolerance test (OGTT) in diagnosing prediabetes. Retrospective review. A total of 224 young people, aged 12.0 years (range: 3.2-17.3 years), with clinical features of insulin resistance, who had an OGTT between 2000 and 2007 at a tertiary children's hospital, Sydney, Australia. Oral glucose tolerance test. A total of 168 (75%) participants had normal glucose tolerance, 45 (20%) had prediabetes and 11 (5%) had type 2 diabetes; 29 of those with prediabetes and 10 with type 2 diabetes were identified by fasting glucose criteria alone. Young people with normal fasting glucose and fasting insulin < or =180 pmol/l had lower insulin resistance (homeostasis model assessment median 1.9 vs. 4.2, P < 0.001), higher insulin sensitivity index (2.4 vs. 1.0, P < 0.001) and a lower early insulin response (insulinogenic index 2.5 vs. 4.1, P < 0.001) compared to those with normal fasting glucose and higher fasting insulin levels. If a fasting insulin cut point (< or =180 pmol/l) was used in addition to fasting glucose to determine the need for an OGTT, 114 (68%) young people with normal glucose tolerance would have avoided the test. By contrast, the diagnosis of impaired glucose tolerance, identified by an OGTT, would have been missed in three children. Fasting glucose and insulin levels should be measured in young people with insulin resistance before undertaking a time- and resource-intensive OGTT.

Glucose metabolism and the risk of Alzheimer’s disease and dementia: a population-based 12 year follow-up study in 71-year-old men

Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.

Aims/hypothesisWe investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity.MethodsWe studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.ResultsThe minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).Conclusions/interpretationGenetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1392-x) contains a list of the members of the RISC Consortium, which is available to authorised users.

Plasma proteome changes in subjects with Type 2 diabetes mellitus with a low or high early insulin response

Circulating proteins contribute to the pathogenesis of T2DM (Type 2 diabetes mellitus) in various ways. The aim of the present study was to investigate variations in plasma protein levels in subjects with T2DM and differences in beta-cell function, characterized by the EIR (early insulin response), and to compare these protein levels with those observed in individuals with NGT (normal glucose tolerance). Ten subjects with NGT+high EIR, ten with T2DM+high EIR, and ten with T2DM+low EIR were selected from the community-based ULSAM (Uppsala Longitudinal Study of Adult Men) cohort. Plasma protein profiling was performed using SELDI-TOF (surface-enhanced laser-desorption ionization-time-of-flight) MS. In total, nine plasma proteins differed between the three study groups (P<0.05, as determined by ANOVA). The levels of two forms of transthyretin, haemoglobin alpha-chain and haemoglobin beta-chain were decreased in plasma from subjects with T2DM compared with subjects with NGT, irrespective of the EIR of the subjects. Apolipoprotein H was decreased in plasma from individuals with T2DM+high EIR compared with subjects with NGT. Four additional unidentified plasma proteins also varied in different ways between the experimental groups. In conclusion, the proteins detected in the present study may be related to the development of beta-cell dysfunction.

Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes

Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function. We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA(1c) in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or > or =50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects. Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14-4.51] vs 4.63 [4.43-4.83] p=0.02) and higher HbA(1c) (4.89% [4.79-4.99] vs 4.68% [4.57-4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA(1c) between the offspring born to mothers and fathers who were diagnosed after the age of 50 years. We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.

Early and late insulin response as predictors of NIDDM in Pima Indians with impaired glucose tolerance

Risk factors predicting deterioration to diabetes mellitus were examined in 181 subjects with impaired glucose tolerance. Fifty-seven subjects had impaired glucose tolerance on one occasion followed by normal glucose tolerance at a repeat oral glucose tolerance test, and 124 subjects had impaired glucose tolerance on two successive oral glucose tolerance tests. Subjects were followed for a median period of 5.0 years (range 1.0-17.2). The age- and sex-adjusted cumulative incidence of diabetes at 10 years of follow-up was higher in subjects who had impaired glucose tolerance on both tests (70%) than in those whose glucose tolerance was normal at the repeat test (53%), [rate ratio (RR) = 1.6, 95% confidence intervals (CI) = 1.0-2.5]. Proportional hazards analyses were used to identify baseline risk factors (measured at the repeat oral glucose tolerance test) for subsequent diabetes, and incidence rate ratios were calculated for the 90th percentile compared with the 10th percentile of each continuous variable for the whole group. In all subjects, in separate models, higher body mass index [RR = 2.0, 95% CI = 2.2-9.9], high fasting serum insulin concentrations [RR = 2.4, 95% CI = 1.4-4.2], and low early insulin response [RR = 0.5, 95% CI = 0.3-0.8] 30 min after a glucose load were significant predictors for deterioration to diabetes. In a multivariate analysis which controlled for age and sex, 120-min post-load glucose, fasting insulin and late insulin response predicted diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity and secretion in healthy elderly human subjects with ‘abnormal’ glucose tolerance

Glucose tolerance deteriorates dramatically with advancing age. It is not known whether the underlying pathophysiology is different in older subjects. We employed a two step hyperinsulinaemic euglycaemic glucose clamp with [6(14)C] glucose infusion to compare peripheral and hepatic insulin sensitivity in eight elderly (EAGT) with eight young (YAGT) subjects with abnormal (matched) glucose tolerance and nine elderly subjects with normal glucose tolerance (ENGT). There was no difference in basal HGO (EAGT 14.5 +/- 0.9, YAGT 15.3 +/- 1.1 mumol kg-1 min-1). Glucose turnover was similar in both groups at step 1 (EAGT 13.2 +/- 0.8, YAGT 13.4 +/- 0.8 mumol kg-1 min-1) and step 2 (EAGT 25.1 +/- 3.1, YAGT 27.2 +/- 2.7 mumol kg-1 min-1). HGO was lower in the EAGT subjects at step 1 (2.3 +/- 0.4 vs. 4.3 +/- 0.6 mumol kg-1 min-1 P = 0.01). Incremental serum insulin response to oral glucose was comparable (EAGT 66.8 +/- 11.6 YAGT 57.8 +/- 12.2 mU l-1.h). Compared to the ENGT group the EAGT group was insulin resistant with a lower MCR of glucose at step 1 (2.03 +/- 0.28 vs. 3.23 +/- 0.44 ml kg-1 min-1 P = 0.04) and at step 2 (6.18 +/- 0.83 vs. 9.64 +/- 0.38 ml kg-1 min-1 P = 0.004) and had a lower early insulin response (AUC 0-30 min 5.9 +/- 1.1 vs. 9.8 +/- 1.4 mU l-1.h P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting Serum Insulin Concentration and Early Insulin Response as Risk Determinants for Developing Diabetes

Among a cohort of 348 women aged 50 on entering a 12-year prospective study, the incidence of diabetes was increased (17.1%) during follow-up in those who initially had fasting glucose concentration above the upper quintile, a fasting serum insulin concentration above the upper quintile (14.9%), a disappearance rate of glucose below the lowest quintile in an IV glucose tolerance test (12.7%), or early insulin response below the lowest quintile (17.1%). The incidence in all women was 4.9%. By multivariate analysis, the highest risk was for high fasting serum insulin concentration. Obesity and treatment with antihypertensive drugs further increased the risk. An initial low early insulin response was not however a prerequisite for the development of manifest diabetes. Determination of fasting insulin concentration, especially in overweight hypertensive subjects, is of value in order to find out which subjects are at high risk of developing diabetes.

Glucose tolerance, insulin release, and insulin sensitivity in normal-weight women with previous gestational diabetes mellitus.

Out of 57 women with previous histories of gestational diabetes (GD), 23 were of normal weight postpartum and willing to participate in three studies characterizing oral glucose tolerance (OGTT), insulin responsiveness to intravenous glucose (glucose infusion test, GIT), and insulin sensitivity (somatostatin, insulin, and glucose infusion test, SIGIT). The experiments were performed 6-36 mo after cessation of breast-feeding. The control group comprised 10 healthy women with normal OGTT matched for age and weight. Among subjects with previous histories of GD, 9 had normal, 8 borderline, and 6 decreased OGTT. As a group, women with previous histories of GD have significantly decreased insulin response and insulin sensitivity. Furthermore, all 14 with borderline and decreased OGTT demonstrated a low early insulin response during GIT (5-min value below the upper border of the lower quartile of normals), whereas insulin sensitivity was normal in 6 and low in 8 (glucose values attained during SIGIT were lower or higher, respectively, than the lower border of the upper quartile of controls). The women with previous histories of GD and normal OGTT exhibited normal (n = 4) and low (n = 5) insulin responses. Three of the former subjects had low and the remaining 6 had normal insulin sensitivity. In conclusion, as many as 60% of normal-weight women with previous histories of GD had borderline or decreased OGTT 6-36 mo postpartum. This derangement could be due to impaired early insulin response, which in some subjects was combined with low insulin sensitivity. Follow-up of women with previous histories of GD might enlighten the pathogenesis of non-insulin-dependent diabetes mellitus.

The question of early insulin response to glucose in patients with ischemic heart disease: a retrospective study in twins. Preliminary communication.

The genetic determination of the early insulin response (EIR) to a standard intravenous glucose load and the relation between EIR and manifestations of ischemic heart disease (IHD) by means of ECG abnormalities was studied in 18 monozygotic (MZ) and 13 dizygotic (DZ) twin pairs aged 53-76 years. Intrapair variances for EIR and basal glucose was significantly smaller in MZ than DZ twins, indicating that genetic factors are of importance for the regulation of these two parameters. No genetic influence on glucose tolerance was found. In DZ twins discordant with respect to pathologic Q waves (Minnesota Code 1.1), significantly lower EIR was found in twin partners with Q wave abnormality. These findings also point to an association between low EIR and IHD.

Early insulin response in latent gestational diabetes.

The intravenous glucose tolerance and glucose-stimulated early insulin response (EIR) were studied in late pregnancy and post partum in a reference (R) group of 9 women and in 18 women with latent gestational diabetes (LD), defined as a k-value of < 0.66/h and a normal fasting blood glucose concentration. During pregnancy, the LD group showed a lower EIR than the R group. However, the response ranged between normal and non-detectable. In the non-pregnant state, the EIR was the same in the two groups. The inability to increase the EIR during pregnancy wss most evident in women who even post partum had an abnormal glucose tolerance. In some women in the LD group, the EIR during pregnancy was even lower than in the non-pregnant state. The magnitude of the response in the non-pregnant state was not decisive of the capacity to increase the secretion during pregnancy. None of the women in the LD group developed manifest diabetes during pregnancy. They gave birth to children with normal birth weight, and no neonatal problems were registered except for one child with congenital heart malformation.

Chapter VIII DIABETES MELLITUS, CARBOHYDRATE TOLERANCE AND EARLY INSULIN RESPONSE TO AN INTRAVENOUS GLUCOSE INJECTION IN A POPULATION SAMPLE OF WOMEN AND IN WOMEN WITH ISCHAEMIC HEART DISEASE

Abstract. The prevalence of manifest diabetes mellitus was significantly higher in women with myocardial infarction than in women in the general population. This was not the case for women with angina pectoris or ECG changes suggestive of ischaemic heart disease. There were no differences in fasting blood glucose or fasting serum insulin values between non‐diabetic women who had angina pectoris or who had had myocardial infarction and non‐diabetic women in the general population. Intravenous glucose injection did not reveal significant differences in glucose tolerance or mean values of early insulin response. However, there was an over‐representation of women with a very low early insulin response in the women who had had myocardial infarction.