Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs

Koopmans, S.J.; Mroz, Z.; Dekker, R.A.; Corbijn, Henk; Ackermans, Mariëtte T.; Sauerwein, Hans P.

doi:10.1016/j.metabol.2006.03.004

Cited by 44 publications

(40 citation statements)

References 51 publications

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“…Insulin resistance for glucose metabolism in diabetic subjects has been argued to be a primary metabolic defect caused by glucose and lipid toxicity [1,17] and insulin hypersensitivity for non-essential AA clearance, as shown in the present study, seems therefore a secondary response, probably a compensatory mechanism to warrant sufficient energy supply to body tissues of diabetic subjects.…”

Section: Discussionsupporting

confidence: 54%

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The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs

et al. 2011

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BackgroundThe generation of energy from glucose is impaired in diabetes and can be compensated by other substrates like fatty acids (Randle cycle). Little information is available on amino acids (AA) as alternative energy-source in diabetes. To study the interaction between insulin-stimulated glucose and AA utilization in normal and diabetic subjects, intraportal hyperinsulinaemic euglycaemic euaminoacidaemic clamp studies were performed in normal (n = 8) and streptozotocin (120 mg/kg) induced diabetic (n = 7) pigs of ~40-45 kg.ResultsDiabetic vs normal pigs showed basal hyperglycaemia (19.0 ± 2.0 vs 4.7 ± 0.1 mmol/L, P < .001) and at the level of individual AA, basal concentrations of valine and histidine were increased (P < .05) whereas tyrosine, alanine, asparagine, glutamine, glutamate, glycine and serine were decreased (P < .05). During the clamp, diabetic vs normal pigs showed reduced insulin-stimulated glucose clearance (4.4 ± 1.6 vs 16.0 ± 3.0 mL/kg·min, P < .001) but increased AA clearance (166 ± 22 vs 110 ± 13 mL/kg· min, P < .05) at matched arterial euglycaemia (5-7 mmol/L) and euaminoacidaemia (2.8-3.5 mmol/L). The increase in AA clearance was mainly caused by an increase in non-essential AA clearance (93.6 ± 13.8 vs 46.6 ± 5.4 mL/kg·min, P < .01), in particular alanine (14.2 ± 2.4 vs 3.2 ± 0.4 mL/kg·min, P < .001). Essential AA clearance was largely unchanged (72.9 ± 8.5 vs 63.3 ± 8.5 mL/kg· min), however clearances of threonine (P < .05) and tyrosine (P < .01) were increased in diabetic vs normal pigs (8.1 ± 1.3 vs 5.2 ± 0.5, and 14.3 ± 2.5 vs 6.4 ± 0.7 mL/kg· min, respectively).ConclusionsThe ratio of insulin-stimulated glucose versus AA clearance was decreased 5.4-fold in diabetic pigs, which was caused by a 3.6-fold decrease in glucose clearance and a 2.0-fold increase in non-essential AA clearance. In parallel with the Randle concept (glucose - fatty acid cycle), the present data suggest the existence of a glucose and non-essential AA substrate interaction in diabetic pigs whereby reduced insulin-stimulated glucose clearance seems to be partly compensated by an increase in non-essential AA clearance whereas essential AA are preferentially spared from an increase in clearance.

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Section: Discussionsupporting

confidence: 54%

“…The pig was chosen as animal model for the study of translational metabolism because of the many similarities between pigs and humans. Both species are of equal size and they are omnivores with similar food intake patterns, digestion and metabolism [17,18]. …”

Section: Introductionmentioning

confidence: 99%

The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs

et al. 2011

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“…In the first step chemical treatment was used to induce diabetes in half of the experimental pigs [12], [13], [23]. This creates an absolute contrast to the not-diabetic control pigs.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma insulin concentration was measured using a Delfia assay (test kit by Perkin Elmer Life Sciences Trust by Wallac Oy, Turku, Finland). This specific pig insulin assay was validated using pig insulin standards, as indicated before [23].…”

Section: Methodsmentioning

confidence: 99%

Plasma Proteome Profiles Associated with Diet-Induced Metabolic Syndrome and the Early Onset of Metabolic Syndrome in a Pig Model

Pas¹,

Koopmans

Kruijt³

et al. 2013

PLoS ONE

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Obesity and related diabetes are important health threatening multifactorial metabolic diseases and it has been suggested that 25% of all diabetic patients are unaware of their patho-physiological condition. Biomarkers for monitoring and control are available, but early stage predictive biomarkers enabling prevention of these diseases are still lacking. We used the pig as a model to study metabolic disease because humans and pigs share a multitude of metabolic similarities. Diabetes was chemically induced and control and diabetic pigs were either fed a high unsaturated fat (Mediterranean) diet or a high saturated fat/cholesterol/sugar (cafeteria) diet. Physiological parameters related to fat metabolism and diabetes were measured. Diabetic pigs' plasma proteome profiles differed more between the two diets than control pigs plasma proteome profiles. The expression levels of several proteins correlated well with (patho)physiological parameters related to the fat metabolism (cholesterol, VLDL, LDL, NEFA) and diabetes (Glucose) and to the diet fed to the animals. Studying only the control pigs as a model for metabolic syndrome when fed the two diets showed correlations to the same parameters but now more focused on insulin, glucose and abdominal fat depot parameters. We conclude that proteomic profiles can be used as a biomarker to identify pigs with developing metabolic syndrome (prediabetes) and diabetes when fed a cafeteria diet. It could be developed into a potential biomarkers for the early recognition of metabolic diseases.

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“…High fat and cholesterol (HFC) diets with or without streptozocin (STZ) have been adapted for the establishment of animal models for type 2 DM, such as pig [7,11,12] and rat [13]. STZ is a chemical that is particularly toxic to insulin-producing pancreatic β-cells in mammals.…”

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confidence: 99%

Development of a type II diabetic mellitus animal model using Micropig®

Lee¹,

Song

Yang³

et al. 2012

Lab Anim Res

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Diabetes, which has shown an explosive increase in terms of its incidence, is regarded as a serious disease that must be overcome for the sake of human life. Among animal models used for testing of drug efficacy, the mini-pig model has shown a rapid upload due to its many similarities with human, particularly concerning the pharmacokinetics of compounds after subcutaneous administration, the structure and function of the gastrointestinal tract, the morphology of the pancreas, and overall metabolic status. Based on these various advantages, we sought to develop an animal model of type II diabetic mellitus using the Micro-pig, which differs from other miniature pigs. We used six male Micro-pigs for induction of a moderate insulin deficient model with nicotinamide (NIA)/streptozotocin (STZ) treatment and three animals for control. For evaluation of incidence of type II diabetes, we measured blood glucose level, and performed oral glucose tolerance test and immunohistochemistry on pancreatic tissue using insulin antibody. Compared to control animals, all animals treated with NIA/STZ showed high levels of glucose and low levels of insulin. In addition, we observed the partially destroyed beta cell population from tissue of the pancreas in treated animals. Based on these results, we report that the Micro-pig model developed in this study can be used for testing of the efficacy of therapeutic agents for treatment of Type 2 diabetic mellitus.

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Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs

Cited by 44 publications

References 51 publications

The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs

The existence of an insulin-stimulated glucose and non-essential but not essential amino acid substrate interaction in diabetic pigs

Plasma Proteome Profiles Associated with Diet-Induced Metabolic Syndrome and the Early Onset of Metabolic Syndrome in a Pig Model

Development of a type II diabetic mellitus animal model using Micropig®

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