Long-term treatment with EXf, a peptide analog of Exendin-4, improves β-cell function and survival in diabetic KKAy mice

To determine the long-term effect of central leptin and resistin on energy homeostasis, peripheral insulin resistance, and β-cell function and mass, intracerebroventricular (ICV) infusion of leptin (3 ng/h), resistin (80 ng/h), leptin plus resistin, and cerebrospinal fluid (control) was conducted by means of an osmotic pump for 4 wk on normal rats and 90% pancreatectomized diabetic rats fed 40% fat-energy diets. Overall, the effects were greater in diabetic rats than normal rats. Leptin infusion, causing a significant reduction in food intake, decreased body weight and epididymal fat. However, resistin and leptin plus resistin reduced epididymal fat with decreased serum leptin levels in comparison with the control. Unlike serum leptin, only resistin infusion lowered serum resistin levels. Central leptin increased glucose infusion rates during euglycemic hyperinsulinemic clamp and suppressed hepatic glucose production in the hyperinsulinemic state in comparison with the control. However, central leptin did not affect glucose-stimulated insulin secretion and β-cell mass. Central resistin infusion also increased peripheral insulin sensitivity, but not as much as leptin. Unlike leptin, resistin significantly increased first-phase insulin secretion during hyperglycemic clamp and β-cell mass by augmenting β-cell proliferation. These metabolic changes were associated with hypothalamic leptin and insulin signaling. ICV infusion of leptin potentiated signal transducer and activator of transcription 3 phosphorylation and attenuated AMP kinase in the hypothalamus, but resistin had less potent effects than leptin. Leptin enhanced insulin signaling by potentiating IRS2→Akt pathways, whereas resistin activated Akt without augmenting insulin receptor substrate 2 phosphorylation. In conclusion, long-term ICV infusion of leptin and resistin independently improved energy and glucose homeostasis by modulating in different ways hypothalamic leptin and insulin signaling.

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Short-term topiramate treatment does not improve insulin sensitivity or secretion in obese insulin-resistant women

Acta Endocrinologica ◽

10.1530/eje-12-0500 ◽

2012 ◽

Vol 167 (6) ◽

pp. 839-845 ◽

Cited By ~ 4

Author(s):

Maria A Sleddering ◽

Marieke Snel ◽

Trea C M Streefland ◽

Hanno Pijl ◽

Ingrid M Jazet

Keyword(s):

Insulin Sensitivity ◽

Infusion Rate ◽

Insulin Infusion ◽

Cell Function ◽

Controlled Study ◽

Β Cell ◽

Insulin Resistant ◽

Insulin Infusion Rate ◽

Long Term Treatment ◽

Β Cell Function

ObjectiveLong-term treatment with topiramate reduces body weight and improves insulin sensitivity in obese humans. Our aim was to evaluate the effect of topiramate treatment for 4 weeks on insulin sensitivity and secretion, independent of weight loss.DesignRandomized, double-blind, crossover, placebo-controlled study.MethodsThirteen obese (BMI 36.6±1.3 kg/m2 (mean±s.e.m.)), insulin-resistant (homeostasis model of assessment-insulin resistance 2.0±0.2) women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 weeks, separated by a 4-week washout period. Insulin sensitivity and β-cell function were assessed using a two-step hyperinsulinemic euglycemic clamp with stable isotopes and a hyperglycemic clamp.ResultsHepatic and peripheral insulin sensitivities were not affected by topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 mU/m2 per min) T: 17.5±0.8 vs P: 18.5±1.0 μmol/kgLBM per min, t=1.016, P=0.33; step 2 (insulin infusion rate 40 mU/m2 per min) T: 27.9±3.2 vs P: 28.8±1.9 μmol/kgLBM per min, t=0.418, P=0.68)). Subjects lost a small amount of weight during the topiramate period (T: −1.0±0.2 vs P: −0.1±0.2 kg, t=2842, P=0.15). There were no changes in body fat mass, blood pressure, and fasting glucose. β-Cell function was not affected by topiramate as evidenced by an unaltered area under the curve of early (0–10 min; T: 1929.6±265.7 vs P: 2024.7±333.6 pmol/l, t=−0.357, P=0.73) and late (80–120 min; T: 28 017.7±5029.9 vs P: 31 567.7±5376.2 pmol/l, t=−1.481, P=0.16) phase insulin levels during hyperglycemia. The use of topiramate was associated with significant side effects such as paresthesia, nausea, dizziness, and concentration problems.ConclusionsLow-dose topiramate treatment for 4 weeks, relative to placebo, had no significant effect on insulin sensitivity in overweight/obese adult females without established diabetes.

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Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0623 ◽

2008 ◽

Vol 93 (9) ◽

pp. 3449-3454 ◽

Cited By ~ 11

Author(s):

Ruben H. Willemsen ◽

Sten P. Willemsen ◽

Anita C. S. Hokken-Koelega

Keyword(s):

Body Composition ◽

Gestational Age ◽

Cell Function ◽

Insulin Response ◽

Fat Distribution ◽

Β Cell ◽

Gh Treatment ◽

Glucose Effectiveness ◽

Β Cell Function

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment. Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment. Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. Outcome Measure: We took paired measurements of Si and β-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and β-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.

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Short- and Long-Term Effects of β-Cellulin and Transforming Growth Factor-α on β-Cell Function in Cultured Fetal Rat Pancreatic Islets

Endocrine ◽

10.1385/endo:11:2:189 ◽

1999 ◽

Vol 11 (2) ◽

pp. 189-194 ◽

Cited By ~ 3

Author(s):

Ake Sjöholm Henrik Kindmark

Keyword(s):

Transforming Growth Factor ◽

Cell Function ◽

Long Term Effects ◽

Β Cell ◽

Transforming Growth Factor Α ◽

Fetal Rat ◽

Β Cell Function ◽

Short And Long Term ◽

Factor Α

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Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic β-cells

Journal of Endocrinology ◽

10.1677/joe-07-0462 ◽

2008 ◽

Vol 197 (2) ◽

pp. 221-229 ◽

Cited By ~ 14

Author(s):

Masaru Koizumi ◽

Toshihiko Yada

Keyword(s):

Glucocorticoid Receptor ◽

Mineralocorticoid Receptor ◽

Term Treatment ◽

Β Cells ◽

Β Cell ◽

Chronic Stimulation ◽

Glucose Signaling ◽

Ru 486 ◽

Long Term Treatment

The development of diabetes associated with stress, obesity, and metabolic syndrome involves elevated plasma glucocorticoid levels. It has been shown that short-term (<1 day) exposure to glucocorticoids reduces insulin secretion from pancreatic islets by affecting several steps of glucose signaling in β-cells. However, longer term direct effects of glucocorticoids on β-cells remain to be established. In this study, single β-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assessment of the β-cell responsiveness to glucose by measuring cytosolic Ca2+ concentration ([Ca2+]i) using fura-2. Following treatment with corticosterone at 10–500 ng/ml for 3 days, the first-phase [Ca2+]i response to 8.3 mM glucose in β-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the β-cell [Ca2+]i response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired β-cell [Ca2+]i responses to glucose. A mineralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca2+]i responses to glucose, while an MR ligand aldosterone attenuated the corticosterone inhibition of [Ca2+]i responses. Neither spironolactone nor aldosterone by itself affected [Ca2+]i responses. These results indicate that long-term treatment with corticosterone impairs β-cell [Ca2+]i responses to glucose. This effect is mediated by GR and attenuated partially by simultaneous MR stimulation by corticosterone. The results show a novel function of MR to protect islet β-cells against deteriorating glucocorticoid action via GR.

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Case Report: Markedly Long-Term Preservation of Pancreatic β‐Cell Function in a Subject With Elderly Onset of Type 1 Diabetes Mellitus Showing High-Titer Autoimmune Antibodies for Over 4 Years

Frontiers in Immunology ◽

10.3389/fimmu.2021.752423 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ryo Shigemoto ◽

Takatoshi Anno ◽

Fumiko Kawasaki ◽

Kohei Kaku ◽

Hideaki Kaneto

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Cell Function ◽

Β Cell ◽

Cell Destruction ◽

Β Cell Function ◽

Long Term Preservation

Type 1 diabetes mellitus (T1DM) is mainly triggered by autoimmune β-cell destruction, usually leading to absolute insulin deficiency. Regarding the speed of β-cell destruction, there are large variations depending on age. In some adult cases, sufficient β-cell function is sometimes retained for a relatively long period and eventually they become dependent on insulin for survival. It is known that even in subjects with T1DM showing high titers of such antibodies, insulin secretory capacity is preserved under several conditions such as “honeymoon” period and slowly progressive T1DM (SPIDDM). Herein, we reported the acute onset T1DM subject with long-term preservation of β-cell function, although his anti-GAD antibody and anti-IA-2 antibody titers were very high for more than 4 years. This case is very important in that his β-cell function was preserved with dipeptidyl peptidase-4 inhibitor alone. This means that there are large variations in the speed of β-cell destruction in the onset of T1DM.

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