Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN β‐cell line and human islets of Langerhans

Hribal, Marta Letizia; Perego, Lucia; Lovari, Sarah; Andreozzi, Francesco; Menghini, Rossella; Perego, Carla; Finzi, Giovanna; Usellini, L.; Placidi, Claudia; Capella, C.; Guzzi, Valeria; Lauro, Davide; Bertuzzi, Federico; Davalli, Alberto M.; Pozza, G.; Pontiroli, Antonio E.; Federici, Massimo; Lauro, Renato; Brunetti, Antonio; Folli, Franco; Sesti, Giorgio

doi:10.1096/fj.02-0685fje

Cited by 61 publications

(59 citation statements)

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“…Although this supports the notion that metabolic syndrome impairs pancreatic insulin secretion, further work is needed to confirm these findings. From our current work, we are unable to determine whether hyperglycemia per se reduces insulin secretion or if a reduction in b-cell function yields elevated blood glucose concentrations, but the mechanism is likely related to the severity of the disease state, 31 physical activity performed, 8 and nutritional background. 9 In addition, gender differences in metabolic syndrome may also contribute to variation in insulin secretion across the glucose tolerance spectrum, although sex did not influence the relationship between metabolic syndrome Z-score and b-cell function in the current study.…”

Section: Discussionmentioning

confidence: 84%

β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults

Malin

Finnegan

Fealy

et al. 2014

Metabolic Syndrome and Related Disorders

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Background: Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic b-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor b-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity). Methods: Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4 -1.1 year; 34.6 -0.6 kg/m 2 ; data are mean -standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I 0-30 / Glc 0-30 or I 60-120 /Glc 60-120 ), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. b-cell function was estimated using the disposition index via HOMA-B/ HOMA-IR, I 0-30 /Glc 0-30 or I 60-120 /Glc 60-120 · Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins. Results: Compared to those with normal glucose tolerance, visceral fat and IR were higher and b-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r = 0.51, r = 0.54, r = -0.49; all P < 0.002, respectively). Basal, first-, and second-phase b-cell function correlated with low Z-scores (r = -0.59, r = -0.51, and r = -0.43, all P < 0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P < 0.005). Conclusion: b-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.

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Section: Discussionmentioning

confidence: 84%

β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults

Malin

Finnegan

Fealy

et al. 2014

Metabolic Syndrome and Related Disorders

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“…glucotoxicity due to uncontrolled diabetes and cytotoxicity by islet amyloid polypeptide (IAPP) [21,22] [23]. Mechanistically, it has also been discussed whether chronic hyperglycemia and different genetic variants of the insulin receptor may affect the clinical course of diabetes [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

et al. 2011

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Aims Both type 1 (T1D) and type 2 (T2D) diabetes are considered to be associated with different degrees of progressive beta cell damage. However, few long term studies have been made. Our aim was to study the clinical course of 20 years of diabetes disease, including diabetes progression, co-morbidity and mortality in a prospectively studied cohort of consecutively diagnosed diabetic patients.Methods Among all 233 patients diagnosed with diabetes during 1985-1987 in Malmö, Sweden, 50 of 118 surviving patients were followed-up after 20 years. The age at diagnose was 42.323.1 and 57.513.6 yrs for antibody positive and antibody negative patients, respectively. HbA1c and plasma lipids were analysed with regard to metabolic control.Results Islet antibody negative patients at diagnosis had highly preserved C-peptide levels after 20 years in contrast to antibody positive patients (antibody-negative: C-peptide 0yrs 0.780.47 and 20yrs 0.700.46 (nmol/l), p=0.51 and antibody-positive: C-peptide 0yrs 0.330.35 and 20yrs 0.100.18; p<0.001. Islet antibodies but not age, BMI or C-peptide at diagnosis were predictors of C-peptide levels at 20 years when analysed by logistic regression (p<0.05). HbA1c did not differ between the groups after 20 years. The 20-year mortality was higher among antibody-negative patients, dependent on the higher age at diagnosis in this group (number of deaths: antibody-positive: 18 of 56 vs. antibody-negative: 109 of 188, p<0.001). Of the deceased, 79 % had died from diseases or complications that may be associated to diabetes. ConclusionWe found no progressive beta cell damage in autoantibody negative diabetes at a 20 year follow-up of the clinical course of diabetes.

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“…Furthermore, chronic hyperglycaemia reduced absolute levels of Insr expression in RIN beta cells and in human islets, but also increased relative abundance of its exon 11+ splicing variant that binds insulin with lower affinity. Specific insulin signalling was decreased and this specific regulation of IR expression and shift in alternative splicing was claimed to play a role in beta cell dysfunction caused by chronic hyperglycaemia [33]. In contrast to IR and IGF-IR, detailed function of IRR that is also strongly regulated by glucose remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

et al. 2005

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Aims/hypothesis: Glucose and the peptide growth factors insulin, IGF-I and IGF-II strongly regulate beta cell mass. Furthermore, beta cell expression of IGF-I receptor (Igf1r) and insulin receptor (Insr) is mandatory for several steps of insulin secretion. Materials and methods: We hypothesised that glucose concentration might regulate expression of Igf1r, Insr and insulin receptor-related receptor (Insrr) in islets and beta cells. Moreover, since the ratio of ATP:ADP is the most important intracellular mechanism involved in insulin secretion, and since depletion of ATP leads to AMP accumulation, we evaluated the role of AMP-activated protein kinase (AMPK) in glucose-dependent receptor regulation. Results: In rat islets, high glucose exposure (25 mmol/l) increased gene expression of Igf1r, Insr and Insrr but also of the metabolic glycolysis gene liver-type pyruvate kinase (Pklr) compared with intermediate (6.2 mmol/l) or low glucose concentration (1.6 mmol/l) after 24 h. In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels. Igf1r expression was suppressed by both high-and low-glucose concentration. Activation of AMPK by 5-amino-imidazolecarboxamide riboside (AICAR, 0.5 mmol/l) suppressed Pklr expression, but strongly stimulated gene expression of Igf1r, Insr and Insrr. Protein expression of IR and IGF-IR reflected glucose and AICARregulated mRNA expression of both receptors in INS-1E cells. Conclusions/interpretation: We conclude that glucose directly interacts with islet and beta cell expression of growth factor receptors that are mandatory for both beta cell growth and insulin secretion. Stimulation of Igf1r and Insr gene expression by the AMPK-activator AICAR might indicate involvement of AMPK in the regulation of Igf1r, Insr and Insrr expression in beta cells.

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Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN β‐cell line and human islets of Langerhans

Cited by 61 publications

References 50 publications

β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults

β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells

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