Insulin Secretion Index Research Articles

ZnT8 autoantibody prevalence is low in youth with type 2 diabetes and associated with higher insulin sensitivity, lower insulin secretion, and lower disposition index

AimZnT8 autoantibody positivity (ZnT8+) is associated with risk for type 1 diabetes and with metabolic complications in adults. Our aim was to assess prevalence of ZnT8 + in the Treatment of T2D in Adolescents and Youth (TODAY) cohort and describe associated phenotypic outcomes. MethodsTODAY participants were 13.98 ± 2.03 years with a confirmed diagnosis of T2D, BMI percentile of 97.69 ± 3.32 (64% female), and GAD- and IA2- at baseline. ZnT8 autoantibodies were measured at baseline and end of study. Results3 of 687 participants (0.29%) were ZnT8 + and there was one conversion (0.15%) from ZnT8- to ZnT8 + during the study. ZnT8A + individuals had higher HbA1c, HDL and LDL cholesterol, and IL-1β concentrations, and lower BMI, IL-6, and triglyceride concentrations compared to the TODAY cohort and ZnT8A- individuals. They also had higher insulin sensitivity with lower insulin secretion and disposition index, metabolically resembling T1D. All ZnT8 + participants experienced loss of glycemic control on randomized treatment, but exhibited lower rates of diabetic complications than other groups. ConclusionGiven the low rate of complications in ZnT8 + individuals, ZnT8 likely does not impact the clinical course of the disease in this population.

Incretin Response to Mixed Meal Challenge in Active Cushing's Disease and after Pasireotide Therapy.

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM–) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study

BackgroundIt has been suggested that fetal sex may be able to modify maternal metabolism and physiology during pregnancy. Recently pregnant women carrying a male fetus were reported to be more insulin sensitive than those carrying females, although related evidence is inconsistent.MethodsIn this study we administered a 75 g oral glucose tolerance test at around week 28 of pregnancy in 813 pregnant women from a contemporary birth cohort (the Cambridge Baby Growth Study), derived surrogate indices of insulin secretion and sensitivity, and related them to the fetal sex.ResultsCarrying a male fetus was associated with lower fasting glucose (difference in mean concentrations ≈ 0.1 mmol/L; β′ = 0.063; p = 0.02) and insulin (≈ 1.1 pmol/L; β′ = 0.075; p = 0.01) concentrations but not with post-load glucose or insulin concentrations. Male fetal sex was also associated with lower HOMA IR (≈ 1.08 units; β′ = 0.071; p = 0.02) and higher QUICKI (≈ 1.06 units; β′ = 0.080; p = 0.007) values suggesting increased basal insulin sensitivity. There were no differences in indices of insulin secretion, except for the insulin disposition index which was higher in women carrying a male fetus (≈ 1.15 units; β′ = 0.090; p = 0.007). Birth weights were higher in male offspring.ConclusionsWomen carrying a male fetus were relatively more insulin sensitive in the fasting state and secreted more insulin relative to this degree of insulin sensitivity. These results are consistent with the idea that the fetal sex may be able to modify the maternal glucose-insulin axis.

Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes

Aims/hypothesisThe aim of this study was to assess the interaction between genetic risk and lifestyle intervention on the occurrence of gestational diabetes mellitus (GDM) and postpartum diabetes.MethodsThe RADIEL study is an RCT aimed at prevention of GDM and postpartum diabetes through lifestyle intervention. Participants with a BMI ≥30 kg/m2 and/or prior GDM were allocated to intervention and control groups before pregnancy or in early pregnancy. The study visits took place every 3 months before pregnancy, once in each trimester, and at 6 weeks and 6 and 12 months postpartum. We calculated a polygenic risk score (PRS) based on 50 risk variants for type 2 diabetes.ResultsAltogether, 516 participants provided genetic and GDM data. The PRS was associated with higher glycaemic levels (fasting glucose and/or HbA1c) and a lower insulin secretion index in the second and third trimesters and at 12 months postpartum, as well as with a higher occurrence of GDM and glycaemic abnormalities at 12 months postpartum (n = 356). There was an interaction between the PRS and lifestyle intervention (p=0.016 during pregnancy and p=0.024 postpartum) when analysing participants who did not have GDM at the first study visit during pregnancy (n = 386). When analysing women in tertiles according to the PRS, the intervention was effective in reducing the age-adjusted occurrence of GDM only among those with the highest genetic risk (OR 0.37; 95% CI 0.17, 0.82). The risk of glycaemic abnormalities at 12 months postpartum was reduced in the same group after adjusting additionally for BMI, parity, smoking and education (OR 0.35; 95% CI 0.13, 0.97).Conclusions/interpretationGenetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk.Clinical trial registrationClinicalTrials.gov identifier: NCT01698385Graphical abstract

HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes.

During progression of type 2 diabetes, pancreatic β cells are subjected to sustained metabolic overload. We postulated that this state mediates a hypoxic phenotype driven by hypoxia-inducible factor-1α (HIF-1α) and that treatment with the HIF-1α inhibitor PX-478 would improve β cell function. Our studies showed that the HIF-1α protein was present in pancreatic β cells of diabetic mouse models. In mouse islets with high glucose metabolism, the emergence of intracellular Ca2+ oscillations at low glucose concentration and the abnormally high basal release of insulin were suppressed by treatment with the HIF-1α inhibitor PX-478, indicating improvement of β cell function. Treatment of db/db mice with PX-478 prevented the rise of glycemia and diabetes progression by maintenance of elevated plasma insulin concentration. In streptozotocin-induced diabetic mice, PX-478 improved the recovery of glucose homeostasis. Islets isolated from these mice showed hallmarks of improved β cell function including elevation of insulin content, increased expression of genes involved in β cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. In response to PX-478 treatment, human islet organoids chronically exposed to high glucose presented improved stimulation index of glucose-induced insulin secretion. These results suggest that the HIF-1α inhibitor PX-478 has the potential to act as an antidiabetic therapeutic agent that preserves β cell function under metabolic overload.

Associations between adherence to the dietary approaches to stop hypertension (DASH) diet and six glucose homeostasis traits in the Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Background and aimsThe DASH diet conveys protection against type 2 diabetes mellitus (T2D) Via plant-based and non-plant-based recommendations. Research has not identified which glucose homeostasis pathways are improved. We examined associations between adherence to a DASH diet and six glucose homeostasis traits, probing whether associations could be attributed to the plant-based (DASH-P) and/or non-plant based (DASH-NP) components. Methods and resultsWe included data from 295 adults without T2D (age 59.3 ± 9.00 years; 63.46% non-Hispanic White and 36.54% African American, self-reported race ancestry) participating in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). An oral glucose tolerance test (OGTT) yielded fasting plasma glucose, insulin, C-peptide, and insulin secretion, sensitivity, and disposition index. Habitual dietary intake was assessed by food frequency questionnaire (FFQ). Associations between DASH components and glucose homeostasis traits were examined, controlling for demographics, body mass index (BMI), physical activity, and energy intake. For significant associations, the models were repeated with scores for DASH-P and DASH-NP as predictors in the same model.DASH and DASH-P scores were inversely associated with fasting plasma glucose (DASH:β = −0.036 ± 0.012,P = 0.005; DASH-P: β = −0.04 ± 0.017,P = 0.002), and positively associated with insulin sensitivity (DASH:β = 0.022 ± 0.012,P = 0.042; DASH-P: = 0.036 ± 0.015,P = 0.014). The DASH score was also associated with disposition index (β = 0.026 ± 0.013,P = 0.038), but this association did not reach significance with DASH-P (β = 0.035 ± 0.018,P = 0.051). No associations were observed with DASH-NP score (all P > 0.05). ConclusionsDASH diet is associated with improvement in specific glucose homeostasis traits, likely arising from increased plant-based foods. Such research may help tailor future dietary advice to specific metabolic risk, and to food groups most effective at improving these.

Lack of Evidence for a Causal Role of Hyperinsulinemia in the Progression of Obesity in Children and Adolescents: A Longitudinal Study.

The carbohydrate-insulin model (CIM) claims that chronic exposure to hyperinsulinemia induced by dietary carbohydrates explains development of obesity via direct effects of insulin and/or low postprandial metabolic fuel levels. We aimed at testing whether indices of hyperinsulinemia and postprandial glucose levels can predict increases in the degree of obesity over time. Children and adolescents with obesity attending a pediatric obesity clinic performed oral glucose tolerance tests (OGTTs) and received standard obesity management. Indices of hyperinsulinemia and insulin secretion were derived from the OGTT and evaluated in the face of changes in the degree of obesity over time. A total of 591 children (217 males and 374 females) participated, and the mean follow-up was 1.86 ± 1.29 years. OGTT-derived area under the curve of insulin, peak insulin, fasting insulin, the insulinogenic index, or insulin at 30 min were not associated with greater changes in the degree of obesity in univariate or multivariate analyses (adjusted for baseline age, BMI z score, sex, and ethnicity). Low postprandial glucose <75 mg/dL was not associated with greater changes in the degree of obesity in univariate or multivariate analyses. In a subsample of 104 participants with a follow-up >4 years, none of these parameters was associated with greater increases in the degree of obesity. In children and adolescents with obesity, exposure to hyperinsulinemia, greater insulin secretion, or low postprandial glucose is not associated with greater increases in the degree of obesity over 2-4 years. The CIM should be evaluated in children with lower BMI and for longer follow-up periods.

Increased serum cystatin C levels and responses of pancreatic α- and β-cells in type 2 diabetes.

BackgroundIncreased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and β-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and β-cell functions in T2D.MethodsIn this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic β-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda’s index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln).ResultsWith quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= –0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (β= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (β= –0.137, t= –7.118, P < 0.001), lnF-GLA (β= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (β= 0.121, t= 5.730, P < 0.001).ConclusionsIncreased serum CysC levels may be partly responsible for increased insulin secretion from β-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.

Pancreatic cancer-associated diabetes mellitus is characterized by reduced β-cell secretory capacity, rather than insulin resistance

AimsThe early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM. MethodsA total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis. ResultsInsulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP. ConclusionsPaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.

Influence of Body Mass Index, Cancer Type and Treatment on Long-Term Metabolic and Liver Outcomes in Childhood Cancer Survivors.

In the last decade, the survival of subjects affected by cancer in childhood has significantly improved. The increased lifespan of childhood cancer survivors (CCS) led to a greater risk for long-term, therapy-related morbidity. To identify the clinical predictors of metabolic adverse outcomes in CCS (average off-therapy period: 12 years), we recruited 126 survivors of different childhood cancers (86.5% hematological cancers) who received at least anticancer chemotherapy, consecutively approached during their annual oncohematological outpatient visit. At examination, anthropometric measures and cancer-related history were collected. Moreover, a fasting venous sample was carried out for measuring fasting plasma glucose and insulin, glycated hemoglobin, lipid panel, and transaminases. We calculated the indexes of insulin resistance (HOMA-IR, McAuley, and QUICKI) and secretion (HOMA-β), liver steatosis (Hepatic Steatosis Index) and fibrosis (FIB-4 and NAFLD fibrosis score), and visceral fat dysfunction (Visceral Adiposity Index). More than one-third of the subjects (37.3%) did not have normal weight, with 11.1% of them affected by obesity. At recruitment, obese subjects were at significantly higher risk for impaired fasting glucose, metabolic syndrome, visceral adipose dysfunction, and liver steatosis/fibrosis. Subjects who received bone marrow transplantation were prone to insulin resistance, while survivors of lymphoma presented a visceral adipose dysfunction These results suggest a carefully metabolic monitoring of CCS, particularly in subgroups at higher risk, to early detect these conditions, promptly begin therapeutic interventions, and mitigate the dysmetabolic-related health burden.

Evaluation of the Efficacies of Liraglutide and Glargine in Type 2 Diabetes Patients with Malignant Tumors Treated with Glucocorticoids

To explore the efficacies of liraglutide and glargine in type 2 diabetes patients with malignant tumors treated with glucocorticoids. Overall, 120 patients were recruited, 60 patients were divided into the glargine group (chemotherapy with glucocorticoids and hypoglycemic therapy including glargine) and 60 patients were divided into the liraglutide group (chemotherapy with glucocorticoids and hypoglycemic therapy including liraglutide). Fasting plasma glucose, 2 h postprandial plasma glucose, glycosylated hemoglobin, body mass index, systolic blood pressure, diastolic blood pressure, C peptide, insulin resistance index, insulin secretion index, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, Karnofsky performance status score, rehospitalization rate, average hospitalization days and adverse reactions before and after intervention were compared between the two groups. After treatment, total cholesterol, highdensity lipoprotein, C peptide, systolic blood pressure, diastolic blood pressure and homeostatic model assessment of insulin resistance were not significantly different between the groups. The body mass index, fasting plasma glucose, 2 h postprandial plasma glucose, glycosylated hemoglobin test (A1c) and homeostasis model assessment of beta cell function were significantly lower in the glargine group than the liraglutide group (p<0.05). The hypoglycemia rate was lower in the liraglutide group than the glargine group (p<0.05). The Karnofsky performance status score was increased (p<0.05) and the rehospitalization rate and average hospitalization days (p<0.05) were decreased in the liraglutide group. Pearson and linear regression analyses indicated that liraglutide treatment was associated with better glucose control, a better homeostasis model assessment of beta cell function, hypoglycemia rate and Karnofsky performance status score and reduced rehospitalization rate and average hospitalization days. Liraglutide treatment significantly improved glucose control, homeostasis model assessment of beta cell function and the hypoglycemia rate and Karnofsky performance status score and reduced the rehospitalization rate and average hospitalization days of type 2 diabetes patients with malignant tumors treated with glucocorticoids.

А PREVALENCE AND RISK FACTORS FOR INSULIN RESISTANCE AND DYSGLYCEMIA AFTER KIDNEY TRANSPLANTATION IN PATIENTS ON CYCLOSPORINE-A BASED IMMUNOSUPPRESSION

Posttransplantation disturbances in glucose metabolism and increased insulin resistance &nbsp;are major factors affecting overall cardiovascular morbidity, reduced graft function, and survival after renal transplantation. We analyzed the prevalence of increased insulin resistance simultaneously with the prevalence of pre-diabetes in kidney transplant patients receiving a Cyclosporine-A based immunosuppression, and analyzed the risk factors for its occurrence, as well as the consequences on graft function. Fifty-nine&nbsp; recipients of a living donor kidney, without previously diagnosed diabetes, were included in this cross-sectional and prospective study. All patients were on the same triple calcineurin inhibitor based immunosuppressive therapy at maintenance doses. In all of them, OGTT was performed at least 6 months after transplantation in order to determine the prevalence of glucose disorders, as well as to determine the indices for insulin resistance and insulin secretion. We also analyzed potential risk factors for their occurrence. According to the OGTT results, patients were divided into two groups: a group with dysglycemia and a group of normoglycemic patients. Graft function was also monitored after a certain follow-up period in both groups. The overall prevalence of glucose disturbances and insulin resistance was 33.9% (20/59) and 86.44% (51/59), respectively. In the group with dysglycemia, the prevalence of insulin resistance was 95% (19/20), while the beta -function index was decreased in 40% (8/20). The mean value of the insulin resistance index in the dysglycemic group was significantly higher (3.139 ± 1.11) compared to the normoglycemic group (2.264±1.00),p ˂0.01. The most significant risk factors for increased insulin resistance in the group with dysglycemia were: shorter transplant period, higher doses of Cyclosporine-A, post-load insulin and the the insulin secretion index. In this group of patients, a significant decrease in e-GFR was observed after an average of 18 months of follow-up. The prevalence of IR after renal transplantation is high in all patients, and especially in patients with disorders of glucose metabolism. The routine application of OGTT as a diagnostic tool for occult diabetes and pre-diabetes and the determination of insulin resistance can contribute to reducing their prevalence, since most of the risk factors for their occurrence are potentially modifiable. Keywords:&nbsp;kidney transplantation, pre-diabetes, insulin resistance, immunosuppression

Changes in serum copeptin in the early onset of type 2 diabetes

Copeptin (C-terminal fragment of pro-arginine vasopressin) levels change as fasting plasma glucose (FPG) and blood pressure change. To explore the clinical significance of changes in copeptin levels in development of type 2 diabetes mellitus (T2DM), we enrolled patients undergoing physical health examinations who met diagnostic criteria for prediabetes and T2DM. Subjects were divided into eight subgroups based on FPG levels and presence or absence of hypertension, including: a normal group (NGT), FPG &lt; 5.6 mmol/L; prediabetes A, 5.6 mmol/L ≤ FPG &lt; 6.1 mmol/L; prediabetes B, 6.1 mmol/L ≤ FPG &lt; 7.0 mmol/L; and T2DM, FPG ≥ 7.0 mmol/L; participants were further into two subgroups by whether they had hypertension or not. Measures included biochemical indicators, fasting insulin (FINS), and copeptin. Copeptin levels in prediabetes A, prediabetes B, and T2DM groups increased significantly compared to NGT group ( P &lt; 0.01). No significant differences were found in copeptin levels between normal blood pressure and hypertension subgroups in all four groups. Copeptin levels correlated positively with systolic blood pressure, glycosylated hemoglobin (HbA1c), FPG, FINS, and insulin resistance index (HOMA-IR; P &lt; 0.05–0.001), and negatively with insulin secretion index ( P &lt; 0.05–0.001). Stepwise regression analysis revealed that copeptin levels correlated independently with elevated HbA1c and aggravated HOMA-IR ( P &lt; 0.001). Increase in copeptin levels may aggravate insulin resistance, finally leading to T2DM.

Glucose variability in subjects with normal glucose tolerance: Relations with body composition, insulin secretion and sensitivity

Background and aimsTo estimate the determinants of glucose variability (GV) in young and middle-aged non-obese subjects with normal glucose tolerance (NGT) we assessed relations between GV parameters, body composition, insulin secretion and sensitivity indices. MethodsThirty individuals with normal body mass index (BMI) and twenty overweight subjects were included. 24-hour mean glucose, time in range, time above range (TAR), time below range (TBR), standard deviation (SD), coefficient of variation (CV), mean amplitude of glucose excursions (MAGE), continuous overlapping net glycemic action (CONGA), J-index, lability index (LI), mean absolute glucose (MAG), M-value, high blood glucose index (HBGI), low blood glucose index (LBGI) were derived from continuous glucose monitoring. Body composition was assessed by DEXA. Insulin secretion and sensitivity was estimated by HOMA-IR and HOMA-B scores. ResultsOverweight subjects demonstrated higher mean glucose, CONGA, J-index and lower TBR, M-value and LBGI values. Mean glucose correlated positively with total, trunk, gynoid and android fat mass, while M-value and LBGI demonstrated negative correlations with these parameters. In multiple stepwise regression analysis, android fat mass was a predictor of mean glucose, CONGA, J-index, SD and MAGE, gynoid fat mass predicted J-index only, and total fat mass was associated inversely with MAG. Fasting insulin was a predictor of TAR, SD, CV, MAGE, MAG, LI and HBGI. HOMA-B was associated with CONGA, M-value and LBGI. ConclusionIn non-obese subjects with NGT mean glucose and GV parameters are related to fat mass and fat distribution. These relations can be mediated through insulin secretion and sensitivity.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n=267, 13-20years), and matched control offspring (n=290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p<0.001 and -6.1%, p=0.006 respectively), but not in index males (2.2%, p=0.476 and -2.4%, p=0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR=0.252 [95% CI 0.085, 0.745], p=0.013 and OR=0.149 [95% CI 0.040, 0.553], p=0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

Pancreatic and gut hormone responses to mixed meal test in post-chronic pancreatitis diabetes mellitus

ObjectiveMore than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls. Design and methodsSixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed. ResultsParticipants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower. ConclusionsPatients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

The Role of Triglyceride to HDL Cholesterol Ratio in Sera as a Clinical Surrogate Marker for Cardiovascular Risk and Insulin Resistance in Patients with Metabolic Syndrome

Summary The study aimed to investigate the triglycerides to HDL-cholesterol ratio (Tg/HDL) and the interaction of this ratio with insulin resistance (IR) and insulin secretion indices, with the levels of interleukin - 1(IL-1), interleukin-6 (Il-6), and tumour necrotic factor-α (TNF-α) in sera among patients with metabolic syndrome (MS). A prospective, cross-sectional, comparative study was conducted on 45 patients with MS without data for hyperglycemia and 21 metabolically healthy non-obese controls. The levels of fasting and postprandial glucose, immunoreactive insulin (IRI), total cholesterol, triglycerides (Tg), IL-1, IL-6, and TNF-α were measured in all the participants. We calculated the LDL cholesterol levels, Tg/HDL ratio, homeostatic model of insulin resistance (HOMA-IR), and the homeostatic model of β-cell function (HOMA-b). Patients with MS had higher BMI (38.73±1.84 vs. 24.32±2.71 kg/m2; р&lt;0.05) and waist circumference (115.56 ±4.7 vs. 81.1±8.4cm; р&lt;0.05) than non-obese controls. The same patients had higher LDL cholesterol levels (3.42±0.3 vs. 2.63±0.66 mmol/l; р&lt;0.05) and Tg (1.59±0.22 vs. 1.08±0.31mmol/l; р&lt;0.05), as well as lower levels of HDL-cholesterol (1.03±0.09 vs. 1.27 ± 0.24mmol/l; р&lt;0.05) compared to the controls. The Tg/HDL ratio was 2.03±0.87 among the patients with MS and 0.88±0.27 in controls; р&lt;0.05. The plasma levels of basal IRI (19.32±3.22 mIU/l vs. 9.13±0.73mIU/l; р&lt;0.05), HOMA-IR (4.02 vs. 1.97; р&lt;0.05) and HOMA-b (258.77±57.76 vs. 183.31±17.52; р&lt;0.05) were significantly higher in the MS group. The same patients with MS had higher concentrations of IL-1 (18.37±4.28pg/ml vs. 7.12±1.74pg/ml; p&lt;0.05), IL-6 (1.01±0.3pg/ml vs. 0.1±0.3pg/ml; р&lt;0.05) and TNF-α (2.13±1.43 pg/ml vs. 1.82±0.94pg/ml; р=0.24) too. Positive correlations between the levels of IL-1 and Tg/HDL ratio (r= 0.46; p=0.008), IL-1 and HOMA-%В (r=0.47; p=0.005) were found. The Tg/HDL ratio is a potential, cheap and available surrogate marker for screening for cardiovascular risk and insulin resistance in patients with MS in clinical practice.

Reproducibility and discrimination of different indices of insulin sensitivity and insulin secretion.

AimsInsulin sensitivity and insulin secretion can be estimated by multiple indices from fasting blood samples or blood samples obtained during oral glucose tolerance tests. The test-retest reliability of these indices in repeated measurements within the same individuals can strongly vary.MethodsWe analyzed data of persons without diabetes who underwent two repeated OGTTs. For each measurement pair, we calculated multiple commonly used indices for the assessment of insulin secretion and insulin sensitivity. We then evaluated the coefficient of variation (standard deviation/mean) and discriminant ratio for each index.Results89 persons underwent two OGTTs with a median interval of 86 days (IQR 64–249). Among indices of insulin sensitivity derived from fasting blood samples, the revised quantitative insulin sensitivity check index had the smallest coefficient of variation (2.8 ± 2.1%) whereas the C-peptide based homeostasis model assessment 2 had the highest discriminant ratio (1.97 (1.65–2.39)). As for insulin sensitivity indices that are based on OGTT, the oral glucose insulin sensitivity index had the smallest coefficient of variation (6.5 ± 5.1%). The highest discriminant ratio was found for the non-esterified fatty acids-based insulin sensitivity index (NEFA-ISI, 2.70 (2.30–3.22)). For the assessment of insulin secretion from fasting variables, the lowest mean coefficient of variation was found for C-peptide based homeostasis model assessment 2 beta with 10.8 ± 8% and the highest discriminant ratio for the C-peptide / Glucose-Ratio (2.18 (1.84–2.63)). Among indices assessing insulin secretion from an OGTT, the lowest coefficient of variation was found for the ratio of the areas under the C-peptide and glucose curves from 0 to 120 minutes with 11.3 ± 9.7%.ConclusionThe data reveal large differences in the reproducibility and the discrimination capability of different indices that assess insulin sensitivity or insulin secretion. Our findings can aid the selection of an appropriate index in clinical studies.

Glucose Metabolism and Insulin Response to Oral Glucose Tolerance Test (OGTT) in Prepubertal Patients with Transfusion-Dependent β-thalassemia (TDT): A Long-Term Retrospective Analysis.

BackgroundGlucose dysregulation (GD), including prediabetes and diabetes mellitus (DM), is a common complication of transfusion-dependent β-thalassemia (TDT) patients. The prevalence increases with age and magnitude of iron overload, affecting a significant proportion of patients. According to the international guidelines, the development of GD is frequently asymptomatic. Therefore, an early diagnosis requires an annual oral glucose tolerance test (OGTT) in all TDT patients aged ten years or older.PurposeThis retrospective study aims to evaluate the prevalence of GD in a homogenous population of prepubertal TDT patients and to enhance understanding of the pathogenesis and progression of glucose homeostasis in this group of patients.MethodsA selected group of 28 TDT patients was followed for at least 10.3 years (range: 10.3 – 28.10 years) from prepubertal age (mean 11.0 ± standard deviation 1.1 years) to adulthood (28.7 ± 3.7 years). Glucose tolerance and insulin response to OGTT were assessed, and indices of β-cell function, insulin sensitivity, and insulin secretion were calculated.ResultsAt baseline, 18 TDT patients had normal glucose tolerance (NGT) and 10 had isolated impaired fasting glycemia (IFG), according to the American Diabetes Association (ADA) criteria. Compared to 18 healthy prepubertal controls (mean ± SD age: 10.9 ± 1.1 years), the fasting plasma glucose (FPG), basal insulin level, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were significantly higher in the group of TDT patients (p= 0.001, 0.01 and 0.012, respectively). At the last observation, 7/18 patients (38.8%) with NGT and 9/10 (90%) with IFG at baseline deteriorated; 3 female patients developed type 2 DM (1 from the NGT group and 2 from the IFG group). Compared to adult controls, TDT patients with NGT had a reduced oral disposition index (DI) (p= 0.006) but no significant difference in HOMA-IR and Matsuda index. Conversely, all insulin indices (HOMA-IR, MI, and DI) but one [insulinogenic index (IGI)] were statistically different in TDT patients with GD compared to controls.ConclusionThis study underlines the concept that the spectrum of glucose tolerance in TDT patients represents a continuum of glucose homeostasis disturbances and that prepubertal patients with IFG are at higher risk of developing a further deterioration of glucose metabolism with time. Moreover, it appears that one-third of adult TDT patients with normal fasting glucose may develop GD in the second-third decade of life. Thus, early intervention could help to prevent an expected further decline of glucose tolerance.

TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.