Development of GDM is characterized by impaired fasting insulin sensitivity and β-cell dysfunction at early gestation

Intro: Adult women with Turner syndrome (TS) have a high prevalence of diabetes and β-cell dysfunction that increases morbidity and mortality, but, it is unknown if there is β-cell dysfunction present in youth with TS. This study aimed to determine the prevalence of β-cell dysfunction in youth with TS and the impact of traditional therapies on insulin sensitivity and insulin secretion. Methods: Cross-sectional, observational study recruited 60 girls with TS and 60 healthy controls (HC) matched on pubertal status. Each subject had a history, physical exam and oral glucose tolerance test (OGTT). Oral glucose and c-peptide minimal modeling was used to determine β-cell function. Results: Twenty-one TS girls (35%) met criteria for pre-diabetes. Impaired fasting glucose (IFG) was present in 18% of girls with TS and 2% HC (p-value = 0.0003). Impaired glucose tolerance (IGT) was present in 23% of TS girls and 0% HC (p-value < 0.001). The HbA1c was not different between TS and HC (median 5%, p= 0.42). Youth with TS had significant reductions in insulin sensitivity (SI), β-cell responsivity (Φ), and disposition index (DI) compared to HC. These differences remained significant when controlling for BMI z-score (p-values: 0.0006, 0.002, <0.0001 for SI, Φtotal, DI, respectively). Conclusions: β-cell dysfunction is present in youth with TS compared to controls. The presence of both reduced insulin secretion and insulin sensitivity suggest a unique TS-related glycemic phenotype. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in TS youth.

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Abstract 1924: Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic Beta Cell Dysfunction

Circulation ◽

10.1161/circ.118.suppl_18.s_406 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Menno Vergeer ◽

Liam R Brunham ◽

Joris Koetsveld ◽

Janine K Kruit ◽

C B Verchere ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Plasma Glucose ◽

Sensitivity Index ◽

Loss Of Function ◽

Β Cell ◽

C Peptide ◽

Cell Dysfunction ◽

Time Interaction

Background The ATP Binding Cassette transporter A1 (ABCA1) transports free cholesterol to nascent high-density lipoproteins (HDL) and maintains plasma HDL levels. In mice, ABCA1 is essential in regulating intracellular cholesterol homeostasis and insulin secretion in the β cell. The role of ABCA1 in human glucose metabolism is unclear. Objective and methods To assess the effects of ABCA1 dysfunction on glucose homeostasis in humans , we matched heterozygous carriers of disruptive mutations in ABCA1 and non-carriers for age, gender and BMI and performed oral glucose tolerance tests (OGTT; 9 vs. 8 respectively) and hyperglycemic clamping experiments (6 vs. 6). Results Carriers had lower HDL-C levels than non-carriers (0.58 ± 0.3 vs. 1.46 ± 0.4 mmol/L, p=0.001) but LDL-C did not differ (3.4 ± 1.0 vs. 2.8 ± 0.8 mmol/L, p=0.21). Fasting plasma glucose was not different (5.2 ± 1.5 vs. 5.0 ± 0.4 mmol/L). Glucose curves after OGTT were significantly higher in carriers than in non-carriers (genotype * time interaction, p=0.005; plasma glucose at t=60 min 9.0 ± 3.0 mmol/L vs. 6.0 ± 1.4 mmol/L respectively, p=0.02). During hyperglycemic clamps, carriers showed a lower first phase insulin and C-peptide response than non-carriers (genotype * time interaction, p<0.05 and p<0.01 respectively; insulin at t=5 min 164±118 vs. 352 ±141 pmol/L, p<0.05; C-peptide at t=5 min 1033 ± 628 vs. 1942 ± 723 pmol/L, p<0.05) but no difference in insulin sensitivity index (0.0216 ± 0.012 mg kg −1 . min −1 . pM −1 for carriers and 0.0197 ± 0.005 mg kg −1 . min −1 . pM −1 for non-carriers; p=0.73). Disposition index - a measure of β cell function, adjusted for insulin sensitivity - was lower in carriers than in non-carriers (1037 ± 610 vs. 2718 ± 1524; p<0.05). Non-carriers responded to an arginine stimulus with an increase in C-peptide levels (from 3558 ± 1240 pM to 6817 ± 1665 pM; p<0.005), whereas in carriers this increase did not reach statistical significance (from 3727 ± 1843 pM to 5480 ± 1757 pM; p=0.12). Conclusion Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance, resulting in glucose intolerance. Our data confirm previous studies in mice and provide evidence for a role of ABCA1 in β cell dysfunction and the pathophysiology of diabetes mellitus in man.

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Association between Genetic Polymorphisms of β-Cell Differentiation Genes and Insulin Resistance (β-Cell Dysfunction) in Childhood Acute Lymphoblastic Leukemia (ALL) Survivors.

Blood ◽

10.1182/blood.v110.11.4281.4281 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4281-4281

Author(s):

Pacharapan Surapolchai ◽

Suradej Hongeng ◽

Samart Pakakasama ◽

Pat Mahachoklertwattana ◽

Angkana Winaichatsak ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Cell Function ◽

Sensitivity Index ◽

Insulin Sensitivity Index ◽

Β Cell ◽

Childhood All ◽

Cell Dysfunction ◽

Β Cell Function

Abstract Background: The purposes of the study were to determine β-cell function and insulin sensitivity after ALL therapy cessation and the association between genetic polymorphisms of β-cell differentiation genes, TCF7L2 and PAX4, with insulin resistance (β-cell dysfunction) in childhood ALL survivors. Methods: Childhood ALL patients diagnosed during 1997–2004 finished the treatment for at least 6 months. The oral glucose tolerance test and lipid screening were performed. Impaired glucose tolerance and diabetes mellitus (DM) were defined according to WHO criteria. β-cell function was estimated by homeostasis model assessment β-cell (HOMA β-cell) and insulinogenic index (IGI) and insulin sensitivity was estimated by whole body insulin sensitivity index (WBISI). The polymorphisms of TCF7L2 (rs12255372 and rs7903146) and PAX4 (A1186C) were genotyped and assessed for the association between these polymorphisms and the β-cell function and the insulin sensitivity. Results: 126 patients were studied (52 females, 74 males and age at the time of study; 4–20 yrs). 116 patients (92%) had normal glucose tolerance (NGT) while the others 10 patients (8%) had impaired glucose tolerance (IGT). Comparing between IGT and NGT groups respectively, we found statistically significant differences in age at the diagnosis (7.5 and 5.2 yrs, p=0.041), age at the study (14 and 10.3 yrs, p=0.001), the duration of post ALL therapy cessation (43 and 26 months, p=0.015), and insulin sensitivity index (WBISI) (5.75 and 9.52, p<0.001). HOMA β-cell and IGI were not different between NGT and IGT group (190.8 and 139.5, p=0.332; 23.6 and 15.8, p=0.310, respectively). Moreover, 32 of 126 patients (25%) had insulin resistance (modified from the criteria of WBISI in obese children and adolescents). These 32 patients who had insulin resistance demonstrated significant pictures of metabolic syndrome i.e. hypertriglyceridemia (116.6 and 85.4 mg/dL, p=0.036), low HDL-C (43.0 and 48.3 mg/dL, p=0.015), obesity (BMI SDS 1.03 and 0.38, p=0.044) and were also older age at the study (12.8 and 9.9 yrs, p<0.001). The genotype frequencies and allele frequencies of polymorphisms of TCF7L2 and PAX4 genes between IGT and NGT groups and between insulin resistance and nonresistance were not difference (p>0.05). Conclusion: The childhood ALL survivors who had IGT were associated with the longer duration of ALL therapy cessation, the older age at diagnosis and at the time of study, and insulin resistance while β-cell function was still relatively preserved. Long-term childhood ALL survivors have potential risks of IGT, insulin resistance and metabolic syndrome. Our findings with such small representatives are not yet applicable to associate TCF7L2 and PAX4 polymorphisms with the insulin resistance (β-cell dysfunction) in the childhood ALL survivors.

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Association of Hematological Parameters with Insulin Resistance and β-Cell Dysfunction in Nondiabetic Subjects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0719 ◽

2009 ◽

Vol 94 (10) ◽

pp. 3824-3832 ◽

Cited By ~ 42

Author(s):

Anthony J. G. Hanley ◽

Ravi Retnakaran ◽

Ying Qi ◽

Hertzel C. Gerstein ◽

Bruce Perkins ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Blood Cell ◽

Cell Count ◽

Hematological Parameters ◽

Sensitivity Index ◽

Blood Cell Count ◽

Β Cell ◽

Cell Dysfunction

Objective: Previous studies reported independent associations of hematological parameters with risk of incident type 2 diabetes, although limited data are available on associations of these parameters with insulin resistance (IR) and (especially) pancreatic β-cell dysfunction in large epidemiological studies. Our objective was to evaluate the associations of hematological parameters, including hematocrit (HCT), hemoglobin (Hgb), red blood cell count (RBC), and white blood cell count with IR and β-cell dysfunction in a cohort of nondiabetic subjects at high metabolic risk. Methods: Nondiabetic subjects (n = 712) were recruited in Toronto and London, Ontario, Canada, between 2004 and 2006, based on the presence of one or more risk factors for type 2 diabetes mellitus including obesity, hypertension, a family history of diabetes, and/or a history of gestational diabetes. Fasting blood samples were collected and oral glucose tolerance tests administered, with additional samples for glucose and insulin drawn at 30 and 120 min. Measures of IR included the homeostasis model assessment (HOMA-IR) and Matsuda’s insulin sensitivity index, whereas measures of β-cell dysfunction included the insulinogenic index divided by HOMA-IR as well as the insulin secretion-sensitivity index-2. Associations of hematological parameters with IR and β-cell dysfunction were assessed using multiple linear regression and analysis of covariance with adjustments for age, gender, ethnicity, smoking, cardiovascular disease, systolic and diastolic blood pressure, and waist circumference. Results: HOMA-IR increased across quartiles of HCT, Hgb, RBC, and white blood cell count after adjustment for age, gender, ethnicity, and smoking (all P (trend) <0.0001). Similarly, there was a strong stepwise decrease in the Matsuda’s insulin sensitivity index across increasing quartiles of these hematological measures (all P (trend) <0.0001). The associations remained significant after further adjustment for previous cardiovascular disease, blood pressure, and waist circumference (all P (trend) <0.0001). Similarly, there was a strong pattern of decreasing β-cell function across increasing quartiles of all hematological patterns (all P (trend) <0.0001). The findings for HCT, Hgb, and RBC were attenuated slightly after full multivariate adjustment, although the trend across quartiles remained highly significant. Conclusion: These findings suggest that standard, clinically relevant hematological variables may be related to the underlying pathophysiological changes associated with type 2 diabetes mellitus. In a large sample of non-diabetic subjects with metabolic risk factors, hematological parameters were significantly associated with insulin sensitivity and β-cell dysfunction, the main physiological disorders underlying type 2 diabetes.

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The effect of high-dose sodium salicylate on chronically elevated plasma nonesterified fatty acid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00313.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E1205-E1211 ◽

Cited By ~ 16

Author(s):

Changting Xiao ◽

Adria Giacca ◽

Gary F. Lewis

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Sodium Salicylate ◽

Insulin Clearance ◽

High Dose ◽

Β Cell ◽

Nonesterified Fatty Acids ◽

Lipid Infusion ◽

Cell Dysfunction ◽

Oral Sodium

Prolonged elevation of plasma nonesterified fatty acids (NEFA) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. Studies in rodents suggest that inflammation may play a role in this “lipotoxicity.” We studied the effects of sodium salicylate, an anti-inflammatory agent, on lipid-induced alterations in β-cell function and insulin sensitivity in six overweight and obese nondiabetic men. Each subject underwent four separate studies, 4–6 wk apart, in random order: 1) SAL, 1-wk placebo followed by intravenous (iv) infusion of saline for 48 h; 2) IH, 1-wk placebo followed by iv infusion of intralipid plus heparin for 48 h to raise plasma NEFA approximately twofold; 3) IH + SS, 1-wk sodium salicylate (4.5 g/day) followed by 48-h IH infusion; and 4) SS, 1-wk oral sodium salicylate followed by 48-h saline infusion. After 48-h saline or lipid infusion, insulin secretion and sensitivity were assessed by hyperglycemic clamp and euglycemic hyperinsulinemic clamp, respectively, in sequential order. Insulin sensitivity was reduced by lipid infusion (IH = 67% of SAL) and was not improved by salicylate (IH + SS = 56% of SAL). Lipid infusion also reduced the disposition index ( P < 0.05), which was not prevented by sodium salicylate. Salicylate reduced insulin clearance. These data suggest that oral sodium salicylate at this dose impairs insulin clearance but does not ameliorate lipid-induced insulin resistance and β-cell dysfunction in overweight and obese nondiabetic men.

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Effects of smoking cessation on β-cell function, insulin sensitivity, body weight, and appetite

Acta Endocrinologica ◽

10.1530/eje-13-0590 ◽

2014 ◽

Vol 170 (2) ◽

pp. 219-227 ◽

Cited By ~ 35

Author(s):

Marietta Stadler ◽

Larissa Tomann ◽

Angela Storka ◽

Michael Wolzt ◽

Slobodan Peric ◽

...

Keyword(s):

Smoking Cessation ◽

Body Weight ◽

Insulin Sensitivity ◽

Cell Function ◽

Oral Glucose ◽

Smoking Abstinence ◽

Fasting Insulin ◽

Cell Secretion ◽

Β Cell ◽

Β Cell Function

ObjectiveTo stop smoking is commonly associated with significant weight gain, but the mechanisms for this are poorly understood. We assessed the effects of smoking cessation on body weight, insulin sensitivity, β-cell function, and appetite.Subjects and methodsTwenty-seven long-term smokers (n=27; nine females/18 males, 28±1 years, 22.9±0.6 kg/m2) attending an ambulatory smoking cessation program in a community hospital in Vienna, Austria were examined at baseline (Visit A; still smoking) and after a minimum of 3 months of smoking abstinence (Visit B;n=14); relapsed smokers were not followed up. Participants underwent 3-h oral glucose tolerance tests and body composition measurements at each study visit. Fasting (QUICKI) and dynamic (oral glucose insulin sensitivity (OGIS)) insulin sensitivity and β-cell secretion (insulinogenic index 140 (IGI40)) were calculated. Food intake was quantified with a free choice buffet. Fasting plasma concentrations of neuropeptide-Y (NPY), peptide-YY (PYY), glucagon-like peptide 1 (GLP1), leptin, ghrelin, and visfatin were measured.ResultsAfter >3 months' smoking abstinence, body weight, and fat mass were increased (+4 and +22% respectively,P<0.05) and fasting insulin sensitivity deteriorated (QUICKI: post, 0.37±0.02 vs baseline, 0.41±0.2;P<0.05), while OGIS remained unchanged throughout. IGI40 increased by 31% after >3 months' smoking abstinence (P<0.01). Carbohydrate ingestion increased after stopping smoking (P<0.05). NPY fasting levels were increased after >3 months (P<0.05), PYY, GLP1, leptin, ghrelin, and visfatin were unchanged.ConclusionSmoking cessation is associated with transient metabolic changes including increased β-cell secretion in response to glucose and fasting insulin resistance. These alterations may be associated with or contribute to the body weight gain after smoking cessation.

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Early impairment of insulin sensitivity, β-cell responsiveness, and insulin clearance in youth with Stage 1 type 1 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab344 ◽

2021 ◽

Author(s):

Alfonso Galderisi ◽

Antoinette Moran ◽

Carmella Evans-Molina ◽

Mariangela Martino ◽

Nicola Santoro ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Plasma Insulin ◽

Cell Function ◽

Insulin Clearance ◽

Fasting Insulin ◽

Β Cell ◽

Stage 1

Abstract Background Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The metabolic phenotypes of beta-cell function and insulin sensitivity and clearance were explored in normoglycemic youth with Stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT). Methods Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-h 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI= φtotal x SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while post-load clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-h OGTT (ISRAUC/IAUC). Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration ≥200mg/dL were excluded. Results Cases (10.5y [8, 15]) exhibited reduced DI (p<0.001) due to a simultaneous reduction in both φtotal (p<0.001) and SI (p=0.008) compared to controls (11.5y [10.4, 14.9]). CL0 and CL180 were lower in cases than controls (p=0.005 and p=0.019). Conclusion Pre-symptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.

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