PS18 - 89. β-cell adaptation is heterogeneous in response to insulin resistance

The perinatal period is critical for β-cell mass establishment, which is characterized by a transient burst in proliferation to increase β-cell mass in response to the need for glucose homeostasis throughout life. In adulthood, the ability of β-cells to grow, proliferate, and expand their mass is also characteristic of pathological states of insulin resistance. Translationally controlled tumor-associated protein (TCTP), an evolutionarily highly conserved protein that is implicated in cell growth and proliferation, has been identified as a novel glucose-regulated survival-supporting protein in pancreatic β-cells. In this study, the enhanced β-cell proliferation detected both during the perinatal developmental period and in insulin-resistant states in high-fat diet-fed mice was found to parallel the expression of TCTP in pancreatic β-cells. Specific knockout of TCTP in β-cells led to increased expression of total and nuclear Forkhead box protein O1 and tumor suppressor protein 53, and decreased expression of p70S6 kinase phosphorylation and cyclin D2 and cyclin-dependent kinase 2. This resulted in decreased β-cell proliferation and growth, reduced β-cell mass, and insulin secretion. Together, these effects led to hyperglycemia. These observations suggest that TCTP is essential for β-cell mass expansion during development and β-cell adaptation in response to insulin resistance.

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β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome

Journal of Endocrinology ◽

10.1530/joe-13-0189 ◽

2013 ◽

Vol 219 (3) ◽

pp. 231-241 ◽

Cited By ~ 31

Author(s):

Liselotte Fransson ◽

Stephanie Franzén ◽

Victoria Rosengren ◽

Petra Wolbert ◽

Åke Sjöholm ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Drinking Water ◽

Mouse Model ◽

Glucose Intolerance ◽

Body Weight Gain ◽

Β Cell ◽

Cell Adaptation ◽

The Metabolic Syndrome ◽

Islet Volume

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.

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β-Cell Adaptation to Insulin Resistance

Journal of Biological Chemistry ◽

10.1074/jbc.m207157200 ◽

2002 ◽

Vol 277 (42) ◽

pp. 39163-39168 ◽

Cited By ~ 106

Author(s):

Ye Qi Liu ◽

Thomas L. Jetton ◽

Jack L. Leahy

Keyword(s):

Insulin Resistance ◽

Β Cell ◽

Cell Adaptation

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Adipose- and muscle-derived Wnts trigger pancreatic β-cell adaptation to systemic insulin resistance

Scientific Reports ◽

10.1038/srep31553 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 12

Author(s):

Kamil Kozinski ◽

Magdalena Jazurek ◽

Pawel Dobrzyn ◽

Justyna Janikiewicz ◽

Katarzyna Kolczynska ◽

...

Keyword(s):

Insulin Resistance ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Adaptation ◽

Systemic Insulin Resistance

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Effects of Ovariectomy on Insulin Resistance and β-Cell Function and Mass

Preventive Nutrition and Food Science ◽

10.3746/jfn.2004.9.4.367 ◽

2004 ◽

Vol 9 (4) ◽

pp. 367-373

Author(s):

Soo-Bong Choi ◽

Chun-Hee Park ◽

Dong-Wha Jun ◽

Jin-Sun Jang ◽

Sun-Min Park

Keyword(s):

Insulin Resistance ◽

Cell Function ◽

Β Cell ◽

Β Cell Function

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Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

Scientific Reports ◽

10.1038/s41598-021-87292-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ionel Sandovici ◽

Constanze M. Hammerle ◽

Sam Virtue ◽

Yurena Vivas-Garcia ◽

Adriana Izquierdo-Lahuerta ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Association Studies ◽

Susceptibility Gene ◽

Chow Diet ◽

Genome Wide Association Studies ◽

Cell Plasticity ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

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Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

Diabetes Epidemiology and Management ◽

10.1016/j.deman.2021.100013 ◽

2021 ◽

pp. 100013

Author(s):

Froylan David Martínez-Sánchez ◽

Valerie Paola Vargas-Abonce ◽

Andrea Rocha-Haro ◽

Romina Flores-Cardenas ◽

Milagros Fernández-Barrio ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

At Risk ◽

Insulin Secretion ◽

Visceral Adiposity ◽

Visceral Adiposity Index ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

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The association of insulinemic potential of diet and lifestyle with the risk of insulin-related disorders: a prospective cohort study among participants of Tehran Lipid and Glucose Study

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00674-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Ebrahim Mokhtari ◽

Hossein Farhadnejad ◽

Farshad Teymoori ◽

Parvin Mirmiran ◽

Fereidoun Azizi

Keyword(s):

Insulin Resistance ◽

Dietary Intakes ◽

Β Cells ◽

Β Cell ◽

Food Frequency ◽

Cell Dysfunction ◽

The Mean ◽

Diet And Lifestyle ◽

Activity Information ◽

Insulin Insensitivity

Abstract Background We aim to assess the association of empirical dietary (EDIH) and lifestyle (ELIH) index for hyperinsulinemia with the risk of insulin resistance, hyperinsulinemia, insulin sensitivity, and β-cell dysfunction in Iranian adults. Methods In this prospective study, a total of 1244 men and women aged ≥ 20 years were selected among participants of the Tehran lipid and glucose study and followed for 3.2 years. Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle insulinemic potential indices were calculated using dietary intake, body mass index, and physical activity information. Multivariable logistic regression was used to estimate the associated risk of a 3-year incidence of insulin-related disorders. Results The mean ± SD age and BMI of all eligible participants (42.7% males) were 43.0 ± 13.0 and 27.4 ± 4.9 in the study's baseline. After adjusting for all potential confounders, participants in the highest tertile of ELIH score had a greater risk of developing hyperinsulinemia (OR:2.42, 95%CI:1.52–3.86, P for trend = < 0.001), insulin resistance (OR:2.71, 95%CI:1.75–4.18, P for trend = < 0.001) and insulin insensitivity (OR:2.65, 95%CI: 1.72–4.10, P for trend = < 0.001) compared with those in the lowest tertile. However, the risk of incident β-cell dysfunction was lower in individuals with a higher score of ELIH in comparison to those with the lowest score (OR:0.30, 95%CI:0.19–0.45, P for trend = < 0.001). Conclusions Empirical lifestyle index for hyperinsulinemia was directly associated with insulin resistance, insulin insensitivity, and hyperinsulinemia and was inversely associated with β-cells dysfunction.

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