Loss of growth hormone signaling in the mouse germline or in adulthood reduces islet mass and alters islet function with notable sex differences

2021 ◽  
Author(s):  
Silvana Duran-Ortiz ◽  
Kathryn L. Corbin ◽  
Ishrat Jahan ◽  
Nicholas B. Whitticar ◽  
Sarah E Morris ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Body Fat ◽  
Isolated Islets ◽  
Wild Type ◽  
Cross Sectional ◽  
Islet Mass ◽  
The Impact

In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared to wild type controls. Also, islets from GHRKO mice secreted ~50% less glucose-stimulated insulin compared to size-matched islets from wild type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at six-months of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12-months of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls while isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism.

Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort

2021 ◽  
pp. 153537022110094
Author(s):  
Ibiye Owei ◽  
Nkiru Umekwe ◽  
Frankie Stentz ◽  
Jim Wan ◽  
Sam Dagogo-Jack
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Intravenous Glucose Tolerance Test ◽  
Cross Sectional ◽  
Parental History ◽  
Intravenous Glucose

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

Increased prevalence of β-cell dysfunction despite normal HbA1c in youth and young adults with Turner Syndrome

2021 ◽  
Author(s):  
Nicole Sheanon ◽  
Deborah Elder ◽  
Jane Khoury ◽  
Lori Casnellie ◽  
Iris Gutmark-Little ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Turner Syndrome ◽  
P Value ◽  
Oral Glucose ◽  
Adult Women ◽  
Β Cell ◽  
Cell Dysfunction ◽  
The Impact

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.

scholarly journals Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Ravneet K. Boparai ◽  
Oge Arum ◽  
Romesh Khardori ◽  
Andrzej Bartke
Keyword(s):  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Endocrine Control ◽  
Cross Sectional ◽  
Systematic Assessment ◽  
Beneficial Effects ◽  
Glucose Stimulated Insulin Secretion ◽  
The Impact

Abstract In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

scholarly journals AMPK subunits harbor largely non-overlapping genetic determinants for body fat mass, glucose- and cholesterol metabolism

2019 ◽  
Author(s):  
Elko Randrianarisoa ◽  
Angela Lehn-Stefan ◽  
Johannes Krier ◽  
Anja Böhm ◽  
Martin Heni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Hdl Cholesterol ◽  
Oral Glucose ◽  
Genetic Determinants ◽  
The Impact

Abstract Context AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all seven subunit genes on adiposity, glucose- and lipid metabolism has not been systematically studied yet. Objective To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-, LDL- and HDL-cholesterol and triglycerides. Study Design and Methods A cohort of 2789 non-diabetic subjects from the Tübingen Family study of type-2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array was analyzed. Results We identified largely non-overlapping SNP sets across four AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total-/LDL-cholesterol or HDL-cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on BMI of +0.22 kg/m² (p=2.3·10-7), insulin sensitivity of -0.12·1019 L²/mol² (p=9.9·10-6) and 2-h blood glucose of +0.02 mmol/L (p=0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total- and LDL-cholesterol by 1.17 mg/dL per allele (p=0.0002 and p=3.2·10-5, respectively), and a genetic HDL score decreased HDL-cholesterol by 0.32 mg/dL per allele (p=9.1·10-6). Conclusions We describe largely non-overlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size.

scholarly journals Glimepiride Administered in Chow Reversibly Impairs Glucose Tolerance in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Dana M. Niedowicz ◽  
Sabire Özcan ◽  
Peter T. Nelson
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Mouse Models ◽  
Fasting Blood Glucose ◽  
Wild Type ◽  
Hypoglycemic Agent ◽  
Dose Dependent ◽  
Type Strains

Sulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no change in circulating glucagon levels or gluconeogenesis. The effect was dose-dependent, took effect by two weeks, and was reversed within three weeks after removal. Glimepiride elicited the same effects in all strains evaluated: four wild-type strains, as well as the transgenic Grn−/− and diabetic db/db mice. Our findings suggest that the use of glimepiride as a hypoglycemic agent in mice should proceed with caution and may have broader implications about mouse models as a proxy to study the human pharmacopeia.

scholarly journals Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

2012 ◽  
Vol 303 (5) ◽  
pp. E587-E596 ◽  
Author(s):  
Lara Bonomi ◽  
Melissa Brown ◽  
Nathan Ungerleider ◽  
Meghan Muse ◽  
Martin M. Matzuk ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Activin A ◽  
Whole Body ◽  
Null Mouse ◽  
Islet Function ◽  
Islet Mass ◽  
Glucose Stimulated Insulin Secretion

Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets.

scholarly journals Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis

2005 ◽  
Vol 152 (2) ◽  
pp. 241-247 ◽  
Author(s):  
Santiago Tofé ◽  
José C Moreno ◽  
Luis Máiz ◽  
Milagros Alonso ◽  
Héctor Escobar ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Nutritional Status ◽  
Pulmonary Function ◽  
Impaired Glucose Tolerance ◽  
Clinical Status ◽  
Assessment Model ◽  
Cross Sectional

Objective: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. Design and methods: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. Results: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n = 9) versus the CF-IGT group (n = 10) and the CF-IGT versus the CF-NGT group (n = 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV1, FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. Conclusions: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.

scholarly journals Body Composition and Markers of Cardiometabolic Health in Transgender Youth Compared With Cisgender Youth

2019 ◽  
Vol 105 (3) ◽  
pp. e704-e714 ◽  
Author(s):  
Natalie J Nokoff ◽  
Sharon L Scarbro ◽  
Kerrie L Moreau ◽  
Philip Zeitler ◽  
Kristen J Nadeau ◽  
...  
Keyword(s):  
Body Composition ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
Lean Mass ◽  
Cross Sectional Study ◽  
Cardiometabolic Health ◽  
Pubertal Stage ◽  
Cross Sectional ◽  
Insulin Resistant ◽  
The Impact

Abstract Context As many as 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic health is unknown. Objective To determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender females (CF) and males (CM). Design Pilot, cross-sectional study conducted from 2016–2018. Setting Academic regional transgender referral center. Participants Transgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI. Main Outcome Measures 1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry). Results Total body fat was lower in TM than CF mean ± SD: (29% ± 7% vs 33% ± 7%; P = 0.002) and higher than in CM (28% ± 7% vs 24% ± 9%; P = 0.047). TM had higher lean mass than CF (68% ± 7% vs 64% ± 7%, P = 0.002) and lower than CM (69% ± 7% vs 73% ± 8%; P = 0.029). Insulin sensitivity was not different between the groups. TF had lower body fat than CF (31% ± 7% vs 35% ± 8%; P = 0.033) and higher than CM (28% ± 6% vs 20% ± 10%; P = 0.001). TF had higher lean mass than CF (66% ± 6% vs 62% ± 7%; P = 0.032) and lower than CM (69% ± 5% vs 77% ± 9%; P = 0.001). TF were more insulin resistant than CM (0.078 ± 0.025 vs 0.142 ± 0.064 mL/μU; P = 0.011). Conclusions Transgender adolescents on GAHT have significant differences in body composition compared with cisgender controls, with a body composition intermediate between BMI-matched CMs and CFs. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents. ClinicalTrials.gov NCT02550431

Sign in / Sign up

Export Citation Format

Share Document