Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

ObjectiveReduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies.Design and methodsIntravenous glucose tolerance tests (IVGTTs) were carried out in 218 children withHLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed.ResultsChildren developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D.ConclusionsYoung age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children withHLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

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Reduced β-cell function in early preclinical type 1 diabetes

Acta Endocrinologica ◽

10.1530/eje-15-0674 ◽

2016 ◽

Vol 174 (3) ◽

pp. 251-259 ◽

Cited By ~ 21

Author(s):

Maarit K Koskinen ◽

Olli Helminen ◽

Jaakko Matomäki ◽

Susanna Aspholm ◽

Juha Mykkänen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Large Population ◽

Cell Mass ◽

Insulin Response ◽

Islet Cell Antibodies ◽

Islet Autoantibodies ◽

Intrinsic Defect ◽

Β Cell ◽

Intravenous Glucose

ObjectiveWe aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity.Design and methodsA large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (≥2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors).ResultsIn the progressors, the first phase insulin response (FPIR) was decreased as early as 4–6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28–75%) and at 10 years: difference 172% (95% CI 128–224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17–58%) and at 10 years: difference 186% (95% CI 143–237%)). Insulin sensitivity did not differ between the groups.ConclusionsFPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in β-cell mass and/or function.

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Food consumption and advanced β cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case-control design

American Journal of Clinical Nutrition ◽

10.3945/ajcn.111.018879 ◽

2012 ◽

Vol 95 (2) ◽

pp. 471-478 ◽

Cited By ~ 59

Author(s):

Suvi M Virtanen ◽

Jaakko Nevalainen ◽

Carina Kronberg-Kippilä ◽

Suvi Ahonen ◽

Heli Tapanainen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Young Children ◽

Food Consumption ◽

Control Design ◽

Case Control ◽

Β Cell ◽

Nested Case Control

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Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00051.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. R757-R762 ◽

Cited By ~ 44

Author(s):

Jaehyek Choi ◽

Cun Li ◽

Thomas J. McDonald ◽

Anthony Comuzzie ◽

Vicki Mattern ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Function ◽

Later Life ◽

Developmental Programming ◽

Glucose Disposal ◽

Model Assessment ◽

Nutrient Reduction ◽

Β Cell ◽

Intravenous Glucose ◽

Pregnancy And Lactation

Developmental programming of postnatal pancreatic β-cell and peripheral insulin function by maternal nutrient reduction (MNR) has been extensively investigated in rodents and sheep, but no data exist from nonhuman primate offspring of MNR mothers. We hypothesized that moderate levels of MNR would result in developmental programming of postnatal β-cell function and peripheral insulin sensitivity that lead to emergence of a prediabetic state prior to puberty. Prepregnancy phenotype of 18 nonpregnant baboons was matched. During pregnancy and lactation 12 mothers ate chow ad libitum (controls), while six ate 70% of chow consumed by controls (weight-adjusted MNR). Weaned offspring ate normal chow. At 3.5 ± 0.18 yr (mean ± SE) in an intravenous glucose tolerance test, conscious, tethered MNR juvenile offspring (2 females and 4 males) showed increased fasting glucose ( P < 0.04), fasting insulin ( P < 0.04), and insulin area under the curve (AUC; P < 0.01) compared with controls (8 females and 4 males). Insulin AUC also increased following an arginine challenge ( P < 0.02). Baseline homeostatic model assessment insulin β-cell sensitivity was greater in MNR offspring than controls ( P < 0.03). In a hyperinsulinemic, euglycemic clamp, the glucose disposal rate decreased 26% in MNR offspring. Changes observed were not sex dependent. MNR in pregnancy and lactation programs offspring metabolic responses, increasing insulin resistance and β-cell responsiveness, resulting in emergence of an overall phenotype that would predispose to later life type-2 diabetes, especially, should other dietary challenges such as a Westernized diet be experienced.

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Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02040 ◽

2017 ◽

Vol 103 (8) ◽

pp. 2870-2878 ◽

Cited By ~ 3

Author(s):

Maarit K Koskinen ◽

Johanna Lempainen ◽

Eliisa Löyttyniemi ◽

Olli Helminen ◽

Anne Hekkala ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Response ◽

Class Ii ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Intravenous Glucose ◽

Hla Dr ◽

Hla Genotype ◽

First Phase Insulin Response

Abstract Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

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Natural History of β-Cell Autoimmunity in Young Children with Increased Genetic Susceptibility to Type 1 Diabetes Recruited from the General Population

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-020018 ◽

2002 ◽

Vol 87 (10) ◽

pp. 4572-4579 ◽

Cited By ~ 99

Author(s):

T. Kimpimäki ◽

P. Kulmala ◽

K. Savola ◽

A. Kupila ◽

S. Korhonen ◽

...

Keyword(s):

Type 1 Diabetes ◽

General Population ◽

Natural History ◽

Young Children ◽

Genetic Susceptibility ◽

Β Cell ◽

History Of

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Type 1 Diabetic Serum Interferes with Pancreatic β-cell Ca2+ -Handling

Bioscience Reports ◽

10.1007/s10540-007-9055-y ◽

2007 ◽

Vol 27 (6) ◽

pp. 321-326 ◽

Cited By ~ 2

Author(s):

N. Dekki ◽

R. Nilsson ◽

S. Norgren ◽

S. M. Rössner ◽

I. Appelskog ◽

...

Keyword(s):

Type 1 Diabetes ◽

Ethnic Background ◽

Diabetic Patients ◽

Pancreatic Β Cell ◽

Newly Diagnosed ◽

Β Cells ◽

Β Cell ◽

First Degree Relatives ◽

Type 1 Diabetic Patients

The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic β-cell cytoplasmic free Ca2+ concentration, [Ca2+]i, and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca2+]i, upon depolarization, were measured in β-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic β-cell Ca2+-handling. This effect on β-cell [Ca2+]i could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca2+-handling may aggravate development of β-cell destruction.

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Urinary PC-1 activity in patients with type 1 diabetes mellitus

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/000456303321610529 ◽

2003 ◽

Vol 40 (3) ◽

pp. 235-238 ◽

Cited By ~ 2

Author(s):

V Stefanovicć ◽

M Rajicć ◽

S Anticć ◽

M Miticć-Zlatkovicć ◽

S Stojiljkovicć ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 1 Diabetes ◽

Urinary Excretion ◽

Type 1 Diabetes Mellitus ◽

Control Level ◽

Diabetic Patients ◽

Potential Factor ◽

Diabetes Patients

Background: Insulin resistance characterizes type 1 diabetes mellitus with nephropathy. The molecular mechanisms of insulin resistance are not completely understood. Recently some advances have been made in identification of transmembrane glycoprotein PC-1 as a potential factor of insulin resistance. Methods: We measured urinary excretion of PC-1 (alkaline phosphodiesterase I), a potential factor of insulin resistance, and N-acetyl-β-D-glucosaminidase (NAGA) in 62 type 1 diabetic patients with different damage to the kidney. Results: In newly detected type 1 diabetes patients, before insulin therapy, urine PC-1 excretion was significantly increased (P<0·05) over the control level. However, in patients after 12·4 years of therapy, urinary PC-1 was significantly decreased (P<0·05). Decreased urine PC-1 activity (P<0·05) was found also in type 1 diabetes patients with microalbuminuria and manifest nephropathy, including those with renal failure. Urinary NAGA excretion was found to be significantly increased (P=0·001) in all but the group of type 1 diabetes patients without nephropathy. Conclusion: This study of urinary PC-1 in patients with type 1 diabetes shows increased excretion in newly detected patients with poor glycaemic control, but decreased excretion in patients with micro-/macroalbuminuria as well as in those without apparent kidney damage. In patients with primary glomerulonephritis, urinary excretion of PC-1 was significantly decreased and that of NAGA significantly increased compared with the excretion in healthy controls.

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Plasma Asprosin Concentrations Are Increased in Individuals with Glucose Dysregulation and Correlated with Insulin Resistance and First-Phase Insulin Secretion

Mediators of Inflammation ◽

10.1155/2018/9471583 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 26

Author(s):

Yuren Wang ◽

Hua Qu ◽

Xin Xiong ◽

Yuyang Qiu ◽

Yong Liao ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Plasma Glucose ◽

Cell Function ◽

Insulin Response ◽

Glucose Regulation ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

Intravenous Glucose ◽

Glucose Dysregulation

Background. Adipokines are reported to participate in many common pathologic processes of glucose dysregulation, such as insulin resistance, β-cell dysfunction, and chronic inflammation. Objective. To detect the concentrations of plasma asprosin in subjects with impaired glucose regulation (IGR) and newly diagnosed type 2 diabetes (nT2DM) and its relationship to parameters of glucose and lipid metabolism, insulin resistance, and pancreatic β-cell function. Methods. 143 eligible participants were included and were divided into three groups including normal glucose regulation (NGR, n=52), IGR (n=40), and nT2DM group (n=51). The intravenous glucose tolerance test (IVGTT) and clinical and biochemical parameters were measured in all participants. Results. Plasma asprosin levels were higher in IGR (82.40 ± 91.06 ng/mL, P<0.001) and nT2DM (73.25 ± 91.69 ng/mL, P<0.001) groups compared with those in the NGR (16.22 ± 9.27 ng/mL) group, especially in IGR subjects. Correlation analysis showed that plasma asprosin levels were positively correlated with waist circumference (Wc), fasting plasma glucose (FPG), postchallenge plasma glucose (2hPG), HbA1c, triglyceride (TG), and homeostasis model assessment for insulin resistance (HOMA-IR) and negatively correlated with homeostasis model assessment for β-cell function (HOMA-β), area under the curve of the first-phase (0–10 min) insulin secretion (AUC), acute insulin response (AIR), and glucose disposition index (GDI) (all P<0.05). Multiple logistical regression analyses revealed that plasma asprosin concentrations were significantly correlated with IGR and nT2DM after controlling for age, sex, BMI, and WHR. Conclusions. Circulating asprosin might be a predictor of early diagnosis in DM and might be a potential therapeutic target for prediabetes and T2DM.

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INSULIN RESISTANCE AND CHRONIC KIDNEY DISEASE IN PATIENTS WITH TYPE 1 DIABETES MELLITUS AT MEDICINE DEPARTMENT OF GMC, BETTIAH, BIHAR

10.36106/ijsr/9227019 ◽

2020 ◽

pp. 1-2

Author(s):

Sumit Kumar ◽

Dharmendra Prasad ◽

Parshuram Yugal ◽

Debarshi Jana

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Chronic Kidney Disease ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Glycosylated Hemoglobin ◽

Diabetic Patients ◽

Medicine Department ◽

Increased Risk

Background and Aims : Diabetes mellitus (DM) is a chronic disease which can evolve towards devastating micro- and macrovascular complications. DM is the most frequent cause of chronic kidney disease (CKD). Insulin resistance plays an important role in the natural history of type 1 diabetes. The purpose of the study was to determine the prevalence of CKD in T1DM and the correlation with insulin resistance (IR) in patients with CKD. Materials and Methods : The study was conducted over a period of two years (2014–2015) and included patients with DM admitted in Medicine Department of ANMMCH, Gaya, Bihar. The study design was an epidemiological, transversal, noninterventional type. Finally, the study group included 200 subjects with type 1 DM. Insulin resistance (IR) was estimated by eGDR. The subjects with eGDR ≤ 7.5mg/kg/min were considered with insulin resistance. Results : CKD was found in 44% of the patients. Analyzing statistically the presence of CKD, we found highly significant differences between patients with CKD and those without CKD regarding age and sex of the patients, the duration of diabetes, glycosylated hemoglobin (HbA1c), the estimated glucose disposal rate (eGDR), and the presence of hypertension, dyslipidemia, and hyperuricaemia. In patients with CKD, age and diabetes duration are significantly higher than in those who do not have this complication. CKD is more frequent in males than in females (50.9% men versus 34.5% women, ). From the elements of metabolic syndrome, high blood pressure, hyperuricemia, and dyslipidemia are significantly increased in diabetic patients with CKD. eGDR value (expressed as mg•kg−1•min−1) is lower in patients with CKD than in those without CKD (15.92 versus 6.42, ) indicating the fact that patients with CKD show higher insulin resistance than those without CKD. Conclusions. This study has shown that insulin resistance is associated with an increased risk of CKD, but, due to the cross-sectional design, the causal relationship cannot be assessed.

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