Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats

There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.

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Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women

American Journal of Clinical Nutrition ◽

10.3945/ajcn.117.152850 ◽

2017 ◽

pp. ajcn152850 ◽

Cited By ~ 8

Author(s):

Otto Savolainen ◽

Mads Vendelbo Lind ◽

Göran Bergström ◽

Björn Fagerberg ◽

Ann-Sofie Sandberg ◽

...

Keyword(s):

Type 2 Diabetes ◽

Food Intake ◽

Glucose Tolerance ◽

Nutrient Status ◽

Glucose Tolerance Status

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Vertical Sleeve Gastrectomy Improves Glucose and Lipid Metabolism and Delays Diabetes Onset in UCD-T2DM Rats

Endocrinology ◽

10.1210/en.2012-1131 ◽

2012 ◽

Vol 153 (8) ◽

pp. 3620-3632 ◽

Cited By ~ 54

Author(s):

Bethany P. Cummings ◽

Ahmed Bettaieb ◽

James L. Graham ◽

Kimber L. Stanhope ◽

Mark Kowala ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Tolerance ◽

University Of California ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Vertical Sleeve Gastrectomy ◽

Diabetes Onset ◽

Oral Glucose Tolerance Tests ◽

Glucose Tolerance Tests

Vertical sleeve gastrectomy (VSG) has gained interest as a low morbidity bariatric surgery, which is effective in producing weight loss and causing type 2 diabetes resolution. However, the efficacy of VSG to prevent the onset of type 2 diabetes has not been previously investigated. VSG or sham surgery was performed on 2-month-old prediabetic male University of California Davis-type 2 diabetes mellitus rats. Sham-operated animals were either sham-operated ad libitum fed (S-AL) or were weight-matched to VSG-operated animals (S-WM). Diabetes onset was determined by weekly nonfasting blood glucose measurements. Animals underwent oral glucose tolerance tests at 1 and 4 months after surgery and indirect calorimetry at 1.5 months after surgery. VSG surgery significantly delayed diabetes onset compared with both S-AL and S-WM animals. VSG-operated animals ate 23% less and weighed 20% less than S-AL. Energy expenditure did not differ between VSG-operated animals and controls. Results from the oral glucose tolerance tests demonstrate improved glucose tolerance and islet function in VSG-operated animals compared with S-AL and S-WM. Nutrient-stimulated glucagon-like peptide (GLP)-1, GLP-2, and peptide YY excursions were greater in VSG-operated animals. VSG surgery resulted in decreased fasting plasma insulin, ghrelin and lipid concentrations, and markedly higher fasting plasma adiponectin and bile acid concentrations, independent of body weight. Increases of circulating bile acid concentrations were due to selective increases of taurine-conjugated bile acids. Thus, VSG delays type 2 diabetes onset in the University of California Davis-type 2 diabetes mellitus rat, independent of body weight. This is potentially mediated by increases of circulating bile acids, adiponectin, and nutrient-stimulated GLP-1 secretion and decreased circulating ghrelin concentrations.

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The joint effect of congenital hypothyroidism and hypercaloric diet consumption as triggers of type 2 diabetes mellitus

European Thyroid Journal ◽

10.1530/etj-21-0050 ◽

2022 ◽

Vol 11 (1) ◽

Author(s):

Jorge Alberto Tapia-Martínez ◽

Margarita Franco-Colín ◽

Vanessa Blas-Valdivia ◽

Edgar Cano-Europa

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adipose Tissue ◽

Cardiovascular Risk ◽

Glucose Tolerance ◽

Congenital Hypothyroidism ◽

Hypercaloric Diet

Introduction Congenital hypothyroidism affects metabolic and thyroid programming, having a deleterious effect on bodyweight regulation promoting metabolic diseases. This work aimed to demonstrate the development of type 2 diabetes mellitus (T2D) in animals with congenital hypothyroidism, only by the consumption of a mild hypercaloric diet in the extrauterine stage. Methods Two groups of female Wistar rats (n = 9): euthyroid and hypothyroid were used. Hypothyroidism was induced by a thyroidectomy with parathyroid reimplantation. Male offsprings post-weaning were divided into four groups (n = 10): euthyroid, hypothyroid, euthyroid + hypercaloric diet, and hypothyroid + hypercaloric diet. The hypercaloric diet consisted of ground commercial feed plus 20% lard and was administered until postnatal week 40. Bodyweight and energy intake were monitored weekly. Also, metabolic and hormonal markers related to cardiovascular risk, insulin resistance, and glucose tolerance were analyzed at week 40. Then, animals were sacrificed to perform the morphometric analysis of the pancreas and adipose tissue. Results T2D was developed in animals fed a hypercaloric diet denoted by the presence of central obesity, hyperphagia, hyperglycemia, dyslipidemia, glucose tolerance, insulin resistance and hypertension, as well as changes in the cytoarchitecture of the pancreas and adipose tissue related to T2D. The results show that congenital hypothyroid animals had an increase in metabolic markers and an elevated cardiovascular risk. Conclusions Congenital hypothyroid animals develop T2D, having the highest metabolic disturbances and a worsened clinical prognosis than euthyroid animals.

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Is visceral fat a better predictor of the incidence of impaired glucose tolerance or type 2 diabetes mellitus than subcutaneous abdominal fat: a systematic review and meta-analysis of cohort studies.

10.7287/peerj.preprints.199v1 ◽

2014 ◽

Author(s):

Ana Valeria B Castro ◽

Vania S Nunes ◽

Viorica Ionut ◽

Richard N Bergman ◽

Regina El Dib

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adipose Tissue ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Subcutaneous Adipose Tissue ◽

Abdominal Fat ◽

Subcutaneous Adipose

BACKGROUND: Several lines of evidence show that abdominal fat is strongly associated with insulin resistance and dysglycemia (impaired glucose tolerance - IGT or type 2 diabetes mellitus - T2DM). However, which component of abdominal fat, subcutaneous or intra-abdominal, has a major impact on the development of insulin resistance and dysglycemia is still a matter of debate. The aim of this review is to summarize the best available evidence on the contribution of subcutaneous and/or intra-abdominal adipose tissues to the incidence of impaired glucose tolerance and/or type 2 diabetes mellitus, in adults as well as to determine which type of abdominal fat is a better predictor of these metabolic disorders. METHODS: A search of published articles on PUBMED (1966 to June 2013), EMBASE (1980 to June 2013), LILACS (1982 to June 2013) and Central Cochrane databases was conducted to identify studies evaluating the relationship between intra-abdominal and/or subcutaneous adipose tissue and the incident IGT or T2DM). Cohort studies examining the association between intra-abdominal and/or subcutaneous adipose tissue values and the prospective development of impaired glucose tolerance or type 2 diabetes mellitus (estimated risk) were included in this review. Data extraction and risk of bias assessments were performed in duplicate by 2 reviewers. Random-effects meta-analyses were performed to pool OR estimates from individual studies to assess the association between intra-abdominal and/or subcutaneous adipose tissue values at baseline and the risk of development of impaired glucose tolerance or type 2 diabetes mellitus. Statistical heterogeneity was assessed using the I2 statistics. The risk of bias was assessed by examining the sample selected, recruitment method, completeness of follow up and blinding according to the guidelines for assessing quality in prognostic studies proposed by Hayden (29) and the MOOSE (30) statement, and adapted by us. RESULTS: Five relevant studies were suitable for this review. The analysis showed that both VAT and abdominal SAT measurements at baseline were strong predictors of incident impaired glucose tolerance or type 2 diabetes mellitus, in minimally adjusted models. However, when other confounding variables besides age, sex and ethnicity were taken into account, VAT, but not SAT, measurements pose a high risk of the incident IGT or T2DM in a wide range of age and ethnic backgrounds (Japanese-, Hispanic-, African-Americans and Canadians). CONCLUSIONS: In conclusion, the present results provide some evidence that VAT imposes more risk to the development of IGT and T2DM than abdominal SAT. However, more studies are necessary to confirm these results and to address the issue of changes in VAT and abdominal SAT and their predictive value regarding IGT and type 2 diabetes developments.

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Buenos Aires, June 2021 Inhibition of Mitochondrial Fission by Drp-1 Blockade by Short-Term Leptin and Mdvi-1 Treatment Improves White Adipose Tissue Abnormalities in Obesity and Diabetes

10.1101/2021.07.23.453523 ◽

2021 ◽

Author(s):

Paola Finocchietto ◽

Hernán Perez ◽

Guillermo Blanco ◽

Verónica Miksztowicz ◽

Clarisa Marotte ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Mitochondrial Dysfunction ◽

White Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Blood Glucose Concentration ◽

Mitochondrial Dynamics ◽

Short Term ◽

Obesity And Diabetes

Background. Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphology abnormalities. Objective . Herein, we investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes. Methods . The effect of short-term leptin and mdivi-1 –a selective inhibitor of Drp-1 fission-protein– treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice. Results . An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p<0.05). The content of mitochondrial DNA and mRNA expression of PGC-1α –both parameters of mitochondrial biogenesis– were reduced in ob/ob mice (p<0.05). Leptin and mdivi-1 treatment signiﬁcantly increased mitochondrial biogenesis, improved fusion-to-ﬁssion balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level. Conclusions. Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes.

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Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance

ISRN Endocrinology ◽

10.1155/2013/148497 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Lisa Arnetz ◽

Neda Rajamand Ekberg ◽

Charlotte Höybye ◽

Kerstin Brismar ◽

Michael Alvarsson

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Acth Stimulation Test ◽

Acth Stimulation ◽

Igf I ◽

Before And After ◽

Subcutaneous Adipose ◽

Pioglitazone Treatment

Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30–45 mg for 12 weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1 μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects () and increased during treatment ( to SD; ); no change was seen in IGT ( SD before and during treatment). Fasting glycerol decreased in T2D (), indicating reduced lipolysis. Fasting cortisol decreased in T2D ( to nmol/L; ) but increased in IGT ( to nmol/L; ). Peak cortisol was lower in T2D during treatment ( to , versus to nmol/L in IGT; ). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT.

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Short-Term Results Suggest That Sleeved Stomach without Resection Is as Effective as Sleeve Gastrectomy in Improving Glucose Control in Type 2 Diabetes Mellitus Sprague-Dawley Rat Model

BioMed Research International ◽

10.1155/2020/9024923 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Wenzhuo Zhang ◽

Jason Widjaja ◽

Libin Yao ◽

Yong Shao ◽

Xiaocheng Zhu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Body Weight ◽

Sleeve Gastrectomy ◽

Food Intake ◽

Glucose Tolerance ◽

Glucose Control ◽

Sprague Dawley ◽

Short Term

Background. Although sleeve gastrectomy results in good weight loss and metabolic improvements, it is an irreversible procedure. Therefore, we attempted to assess the possibility of creating a sleeved stomach without resection. Material and Methods. A total of 22 male Sprague-Dawley rats with type 2 diabetes were randomly assigned into 3 different groups: (1) sleeve gastroplasty with gastric remnant-jejunal anastomosis (SGP, n=8); (2) sleeve gastrectomy (SG, n=8); and (3) SHAM (n=6). Body weight, food intake, fasting blood glucose (FBG), hormonal analysis, and oral glucose tolerance test (OGTT) were performed and measured preoperatively and postoperatively. Results. During the postoperative period, SGP and SG showed significantly lower food intake and body weight when compared with the preoperative levels, respectively (p value < 0.05). Postoperatively, SGP and SG showed improvements in FBG and glucose tolerance levels compared to their respective preoperative levels (p<0.05). FBG and glucose tolerance levels did not differ between SGP and SG postoperatively. SG resulted in a reduction in fasting ghrelin levels when compared with the preoperative level (p<0.05). Fasting insulin levels did not differ preoperatively and postoperatively among all groups. Postoperatively, fasting GLP-1 levels were higher in SGP and SG when compared with the preoperative levels, but no statistical significance was observed. Compared preoperatively, the SGP and SG procedures resulted in a decline in HOMA-IR at postoperative 6th week (p<0.05). Conclusion. Our animal experiment suggested that at least in the short term, sleeved stomach without resection resulted in similar weight loss and improved glucose control effects compared to sleeve gastrectomy.

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