Chickens genetically selected for high or low juvenile body weight display differences in glucose tolerance and insulin sensitivity

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

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Chronic Central Leptin Decreases Food Intake and Improves Glucose Tolerance in Diet-Induced Obese Mice Independent of Hypothalamic Malonyl CoA Levels and Skeletal Muscle Insulin Sensitivity

Endocrinology ◽

10.1210/en.2011-1254 ◽

2011 ◽

Vol 152 (11) ◽

pp. 4127-4137 ◽

Cited By ~ 7

Author(s):

Wendy Keung ◽

Arivazhagan Palaniyappan ◽

Gary D. Lopaschuk

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Energy Metabolism ◽

Food Intake ◽

Glucose Tolerance ◽

Tolerance Test ◽

Acid Oxidation ◽

Obese Mice ◽

Malonyl Coa ◽

Skeletal Muscle Insulin Sensitivity

Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice.

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Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

Journal of Endocrinology ◽

10.1530/joe-17-0263 ◽

2017 ◽

Vol 234 (3) ◽

pp. 255-267 ◽

Cited By ~ 26

Author(s):

Paul Millar ◽

Nupur Pathak ◽

Vadivel Parthsarathy ◽

Anthony J Bjourson ◽

Maurice O’Kane ◽

...

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Energy Intake ◽

Diabetic Mice ◽

Neuroprotective Effects ◽

Once Daily ◽

Stratum Pyramidale ◽

Sodium Glucose Cotransporter ◽

Neuroprotective Actions

This study assessed the metabolic and neuroprotective actions of the sodium glucose cotransporter-2 inhibitor dapagliflozin in combination with the GLP-1 agonist liraglutide in dietary-induced diabetic mice. Mice administered low-dose streptozotocin (STZ) on a high-fat diet received dapagliflozin, liraglutide, dapagliflozin-plus-liraglutide (DAPA-Lira) or vehicle once-daily over 28 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, hormone and biochemical analysis, dual-energy X-ray absorptiometry densitometry, novel object recognition, islet and brain histology were examined. Once-daily administration of DAPA-Lira resulted in significant decreases in body weight, fat mass, glucose and insulin concentrations, despite no change in energy intake. Similar beneficial metabolic improvements were observed regarding glucose tolerance, insulin sensitivity, HOMA-IR, HOMA-β, HbA1c and triglycerides. Plasma glucagon, GLP-1 and IL-6 levels were increased and corticosterone concentrations decreased. DAPA-Lira treatment decreased alpha cell area and increased insulin content compared to dapagliflozin monotherapy. Recognition memory was significantly improved in all treatment groups. Brain histology demonstrated increased staining for doublecortin (number of immature neurons) in dentate gyrus and synaptophysin (synaptic density) in stratum oriens and stratum pyramidale. These data demonstrate that combination therapy of dapagliflozin and liraglutide exerts beneficial metabolic and neuroprotective effects in diet-induced diabetic mice. Our results highlight important personalised approach in utilising liraglutide in combination with dapagliflozin, instead of either agent alone, for further clinical evaluation in treatment of diabetes and associated neurodegenerative disorders.

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Deficiency in Interferon-γ Results in Reduced Body Weight and Better Glucose Tolerance in Mice

Endocrinology ◽

10.1210/en.2011-0288 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3690-3699 ◽

Cited By ~ 41

Author(s):

Nicole Wong ◽

Barbara C. Fam ◽

Gitta R. Cempako ◽

Gregory R. Steinberg ◽

Ken Walder ◽

...

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Food Intake ◽

Glucose Metabolism ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Mrna Expression ◽

Tolerance Test ◽

Interferon Γ ◽

Reduced Body

Obesity is a chronic low-grade inflammatory disease caused by increased energy intake and reduced energy expenditure. Studies using animal models with deletion of inflammatory cytokines have produced conflicting results with some showing increased weight gain and others showing no effect or even reduced body weights. Clearly, more work is necessary to understand the role of cytokines on body weight control. The aim of this study was to determine the effect of interferon-γ deletion (IFNγ−/−) on body weight regulation and glucose metabolism. Male IFNγ−/− and wild-type C57BL/6 mice were fed a low-fat chow diet, and body weight, food intake, and energy expenditure were monitored over 20 wk. At the end of the study, ip glucose tolerance test, insulin tolerance test, basal glucose turnover, and hyperinsulinemic/euglycemic clamps were performed. Expression levels of arcuate nucleus neuropeptide Y, Agouti-related peptide, and proopiomelanocortin mRNA as well as circulating leptin levels were also determined. IFNγ−/− mice had improved glucose tolerance with reduced rate of glucose appearance and increased insulin sensitivity due to greater suppression of endogenous glucose output, which was associated with decreased hepatic glucose-6-phosphatase activity. In addition, we also observed reduced body weight associated with decreased food intake and increased physical activity. Neuropeptide Y and Agouti-related peptide mRNA expression was reduced, whereas proopiomelanocortin mRNA expression was increased, as were plasma leptin levels. Global deletion of IFNγ in mice resulted in reduced body weight associated with negative energy balance, improved glucose tolerance, and hepatic insulin sensitivity. Our findings demonstrate that IFNγ plays a critical role in the regulation of body weight and glucose metabolism.

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Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00525.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. G751-G760 ◽

Cited By ~ 37

Author(s):

Derek M. Culnan ◽

Vance Albaugh ◽

Mingjie Sun ◽

Christopher J. Lynch ◽

Charles H. Lang ◽

...

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Food Intake ◽

Glucose Tolerance ◽

Glucose Uptake ◽

Zucker Rats ◽

Ileal Interposition ◽

Obese Zucker Rat ◽

Obese Zucker Rats ◽

Glucagon Like Peptide 1

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group ( P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[14C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt ( P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

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Contribution of Gestational Weight Gain on Maternal Glucose Metabolism in Women with GDM and Normal Glucose Tolerance

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa195 ◽

2020 ◽

Author(s):

Fernanda L Alvarado ◽

Perrie O’Tierney-Ginn ◽

Patrick Catalano

Keyword(s):

Body Composition ◽

Body Weight ◽

Weight Gain ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Normal Glucose Tolerance ◽

Gestational Weight ◽

Normal Glucose ◽

The Relationship

Abstract Context Efforts to decrease the risk of developing metabolic complications of pregnancy such as gestational diabetes (GDM) through lifestyle intervention (decreasing excessive gestational weight gain (GWG)) during pregnancy have met with limited success. Objective The purpose of this study was to determine the relationship between the longitudinal changes in weight/body composition and insulin sensitivity and response in women with normal glucose tolerance (NGT) and those who developed GDM. Design We conducted a secondary analysis of a prospective cohort developed before conception and again at 34-36 weeks gestation. Twenty-nine NGT and seventeen GDM women were evaluated for longitudinal changes in insulin sensitivity/response using the hyperinsulinemic-euglycemic clamp and an IV-glucose tolerance test. Body composition was estimated using hydrodensitometry. Both absolute (Δ) and relative change (%Δ) between these two time points were calculated. We performed simple and multiple linear regression analysis to assess the relationship between GWG and measures of glucose metabolism, i.e. insulin sensitivity and response. Results Based on the primary study design there was no significant difference in clinical characteristics between women with NGT and those developing GDM. Prior to pregnancy, women who developed GDM had lower insulin sensitivity levels (p=0.01) compared to NGT women. Absolute change and %Δ in insulin sensitivity/insulin response and body weight/body composition was not significantly different between NGT and GDM women. Changes in body weight contributed to only 9% of the Δ insulin sensitivity both in women developing GDM and NGT women. Conclusions These data suggest that other factors – such as maternal pre-pregnancy insulin sensitivity and placental derived factors affecting insulin sensitivity rather than maternal GWG account for the changes in glucose metabolism during human pregnancy.

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Low doses of cocoa extract supplementation ameliorate diet-induced obesity and insulin resistance in rats

Food & Function ◽

10.1039/c9fo00918c ◽

2019 ◽

Vol 10 (8) ◽

pp. 4811-4822 ◽

Cited By ~ 4

Author(s):

Paula Aranaz ◽

Ana Romo-Hualde ◽

David Navarro-Herrera ◽

María Zabala ◽

Miguel López-Yoldi ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Body Weight ◽

Weight Gain ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Body Weight Gain ◽

Liver Steatosis ◽

Low Doses ◽

Diet Induced Obesity

Supplementation with low doses of a cocoa extract induces metabolic benefits in the prevention of metabolic syndrome in rats, reducing body-weight gain, visceral adiposity and liver steatosis and improving insulin sensitivity and glucose tolerance.

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Assessing the utility of cardiorespiratory fitness, visceral fat, and liver fat in predicting changes in insulin sensitivity beyond simple changes in body weight after exercise training in adolescents

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2020-0284 ◽

2021 ◽

Vol 46 (1) ◽

pp. 55-62

Author(s):

Jennifer L. Kuk ◽

SoJung Lee

Keyword(s):

Body Composition ◽

Body Weight ◽

Insulin Sensitivity ◽

Exercise Training ◽

Glucose Tolerance ◽

Weight Change ◽

Visceral Fat ◽

Liver Fat ◽

Body Weight Change ◽

Sensitivity Changes

To examine the utility of changes in cardiorespiratory fitness (CRF) and body composition in response to exercise training in adolescents with obesity beyond simple measures of body weight change. This is a secondary analysis of our previously published randomized trials of aerobic, resistance, and combined training. We included 104 adolescents (body mass index (BMI) ≥85th percentile) who had complete baseline and post-intervention data for CRF, regional body fat, insulin sensitivity, and oral glucose tolerance. Associations between changes in body composition and CRF with cardiometabolic variables were examined adjusted for age, sex, Tanner stage, race, exercise group, and weight loss. At baseline, CRF, visceral fat and liver fat were correlated with insulin sensitivity with and without adjustment for BMI percentile. Training-associated changes in CRF, visceral fat, and liver fat were also correlated with insulin sensitivity changes, but not independent of body weight change. After accounting for body weight change, none of the body composition or CRF were associated with changes in insulin sensitivity, glucose tolerance, systolic blood pressure, or high-density lipoprotein cholesterol. Although CRF and body composition were strong independent correlates of insulin sensitivity at baseline, changes in CRF and visceral fat were not associated with changes in insulin sensitivity after accounting for body weight change. Clinicaltrials.gov registration nos.: NCT00739180, NCT01323088, NCT01938950. Novelty With exercise training, changes in body weight, CRF, visceral fat, and liver fat were correlated with changes in insulin sensitivity. Changes in body composition or CRF generally did not remain significant correlates of changes in insulin sensitivity after adjusting for body weight changes.

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Abstract 018: Neuronal (Pro)renin Receptor Deletion Prevents High-fat Diet Induced High Blood Pressure and Type II Diabetes

Hypertension ◽

10.1161/hyp.70.suppl_1.018 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Caleb J Worker ◽

Wencheng Li ◽

Yumei Feng

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Body Weight ◽

Insulin Sensitivity ◽

Angiotensin Ii ◽

Glucose Tolerance ◽

High Fat Diet ◽

Fasting Blood Glucose ◽

Renin Angiotensin System ◽

High Fat

We recently reported that the (pro)renin receptor (PRR) is a key component of the brain renin-angiotensin system, mediating the majority of Ang II formation, and plays a pivotal role in the development of hypertension. Its importance in obesity-related metabolic syndrome is, however, unknown. We hypothesize that brain PRR plays a regulatory role in high-fat diet (HFD) induced metabolic syndrome. To test our hypothesis, neuron-specific PRR knockout (PRRKO) mice and wildtype (WT) littermates were fed with either HFD (60% calories from fat) or normal fat chow (NFD, 10% calories from fat) with matching calories for 16 weeks. Weekly body weight (BW) and monthly fasting blood glucose (FBG) measurements were recorded and end point glucose tolerance (GTT) and insulin sensitivity tests (IST) were performed. Blood pressure (BP) was recorded using radiotelemetry in conscious free moving mice. We observed no difference in BW or food intake between genotypes in either HFD or NFD. The baseline BP and heart rate (HR) were similar between PRRKO and WT mice; however, following 16 weeks HFD the BP (101±6 vs. 111±3 mmHg, P=0.035) and HR (536±12 vs. 578±4 BPM, P=0.046) were significantly lower in PRRKO compared with WT mice. Interestingly, neuronal PRR deletion attenuated the elevation of FBG (127.12±10.46 vs. 167.77±16.57 mg/dl, P=0.039) induced by HFD. Glucose tolerance was significantly improved in PRRKO compared with WT following 16 weeks of HFD (AUC: 20557±894 vs. 29994±2976, P=0.006), while there was no difference in the IST between the groups. We also found that HFD mice had higher levels of plasma (pro)renin (9.95±1.83 vs. 2.74± 0.47 ng/ml, P=0.005) and brain angiotensin II (656.8±94.9 vs. 375.3±32.0 pg/g, P=0.02), as well as higher cardiac (ΔHR to propranolol: -150±6 vs. -82±15 bpm , P=0.0054) and vasomotor (ΔBP to chlorisondamine: -44±3 vs. -22±3 mmHg, P=0.0004) sympathetic tone, suggesting that the HFD-induced rise in BP is sympathetically mediated and associated with elevation of brain angiotensin II. Our data indicates that PRR deletion in the neurons protects against glucose intolerance and BP elevation in HFD mice with no effect on insulin sensitivity or body weight. We conclude that neuronal PRR plays a role in the development of obesity-related metabolic syndrome.

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