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DOI: 10.1055/s-0030-1248251
© Georg Thieme Verlag KG Stuttgart · New York
10-Day Hyperlipidemic Clamp in Cats: Effects on Insulin Sensitivity, Inflammation, and Glucose Metabolism-related Genes
Publication History
received 13.10.2009
accepted 18.01.2010
Publication Date:
16 February 2010 (online)

Abstract
Obesity and hyperlipidemia are associated with impaired insulin sensitivity in human type 2 diabetes mellitus, possibly due to activation of a mild inflammatory response. Because obesity-induced insulin resistance predisposes cats to diabetes and because hyperlipidemia is a frequent concurrent finding, excess lipids may also impair insulin sensitivity in cats. Healthy cats (n=6) were infused with lipids (LipovenoesR 10%) for 10 days to clamp blood triglycerides at the approximate concentration of untreated feline diabetes (3–7 mmol/l). Controls received saline (n=5). On day 10, plasma adiponectin and proinflammatory markers were measured. Whole-body insulin sensitivity was calculated following an intravenous glucose tolerance test. Tissue mRNAs of glucose metabolism-related genes were quantified in subcutaneous and visceral fat, liver, and skeletal muscles. Accumulation of lipids was assessed in liver. At the termination of infusion, whole-body insulin sensitivity did not differ between groups. Compared to saline, cats infused with lipids had 50% higher plasma adiponectin and 2–3 times higher α1-acid glycoprotein and monocyte chemoattractant protein-1. Unexpectedly, lipid-infused cats had increased glucose transporter-4 (GLUT4) mRNA in the visceral fat, and increased peroxisome proliferative activated receptor-γ2 (PPARγ2) in subcutaneous fat; adiponectin expression was not affected in any tissue. Lipid-infused cats developed hepatic steatosis. Although hyperlipidemia induced systemic inflammation, whole-body insulin sensitivity was not impaired after 10 day infusion. Increased circulating adiponectin may have contributed to prevent insulin resistance, possibly by increasing GLUT4 and PPARγ2 transcripts in fat depots.
Key words
feline - lipid infusion - adiponectin - inflammation
References
- 1
Lutz TA, Rand JS.
Pathogenesis of feline diabetes mellitus.
Vet Clin North Am Small Anim Pract.
1995;
25
527-552
MissingFormLabel
- 2
Cefalu WT.
Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance
to the human condition.
ILAR J.
2006;
47
186-198
MissingFormLabel
- 3
Henson MS, O’Brien TD.
Feline models of type 2 diabetes mellitus.
ILAR J.
2006;
47
234-242
MissingFormLabel
- 4
McGarry JD.
Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.
Diabetes.
2002;
51
7-18
MissingFormLabel
- 5
Greenfield JR, Campbell LV.
Relationship between inflammation, insulin resistance and type 2 diabetes: cause or
effect?.
Curr Diabetes Rev.
2006;
2
195-211
MissingFormLabel
- 6
Fabris R, Nisoli E, Lombardi AM, Tonello C, Serra R, Granzotto M, Cusin I, Rohner-Jeanrenaud F, Federspil G, Carruba MO, Vettor R.
Preferential channeling of energy fuels toward fat rather than muscle during high
free fatty acid availability in rats.
Diabetes.
2001;
50
601-608
MissingFormLabel
- 7
Park E, Wong V, Guan X, Oprescu AI, Giacca A.
Salicylate prevents hepatic insulin resistance caused by short-term elevation of free
fatty acids in vivo.
J Endocrinol.
2007;
195
323-331
MissingFormLabel
- 8
Lavoie F, Frisch F, Brassard P, Normand-Lauzière F, Cyr D, Gagnon R, Drouin R, Baillargeon JP, Carpentier AC.
Relationship between total and high molecular weight adiponectin levels and plasma
nonesterified fatty acid tolerance during enhanced intravascular triacylglycerol lipolysis
in men.
J Clin Endocrinol Metab.
2009;
94
998-1004
MissingFormLabel
- 9
Meshkani R, Adeli K.
Hepatic insulin resistance, metabolic syndrome and cardiovascular disease.
Clin Biochem.
2009;
42
1331-1346
MissingFormLabel
- 10
Xiao C, Giacca A, Lewis GF.
Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin
sensitivity and beta cell function in obese and overweight, non-diabetic men.
Diabetologia.
2008;
51
139-146
MissingFormLabel
- 11
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS.
TLR4 links innate immunity and fatty acid-induced insulin resistance.
J Clin Invest.
2006;
116
3015-3025
MissingFormLabel
- 12
Wellen KE, Hotamisligil GS.
Inflammation, stress, and diabetes.
J Clin Invest.
2005;
115
1111-1119
MissingFormLabel
- 13
Semple RK, Chatterjee VK, O’Rahilly S.
PPAR gamma and human metabolic disease.
J Clin Invest.
2006;
116
581-589
MissingFormLabel
- 14
Fabris R, Nisoli E, Lombardi AM, Tonello C, Serra R, Granzotto M, Cusin I, Rohner-Jeanrenaud F, Federspil G, Carruba MO, Vettor R.
Preferential channeling of energy fuels toward fat rather than muscle during high
free fatty acid availability in rats.
Diabetes.
2001;
50
601-608
MissingFormLabel
- 15
Reusch CE, Haberer B.
Evaluation of fructosamine in dogs and cats with hypo- or hyperproteinaemia, azotaemia,
hyperlipidaemia and hyperbilirubinaemia.
Vet Rec.
2001;
148
370-376
MissingFormLabel
- 16
Han P, Zhang YY, Lu Y, He B, Zhang W, Xia F.
Effects of different free fatty acids on insulin resistance in rats.
Hepatobiliary Pancreat Dis Int.
2008;
7
91-96
MissingFormLabel
- 17
Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K.
Dose-response effect of elevated plasma free fatty acid on insulin signaling.
Diabetes.
2005;
54
1640-1648
MissingFormLabel
- 18
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI.
Mechanism of free fatty acid-induced insulin resistance in humans.
J Clin Invest.
1996;
97
2859-2865
MissingFormLabel
- 19
Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Fürnsinn C, Moser E, Waldhäusl W.
Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty
acids in humans.
Diabetes.
1999;
48
358-364
MissingFormLabel
- 20
Zini E, Osto M, Franchini M, Guscetti F, Donath MY, Perren A, Heller RS, Linscheid P, Bouwman M, Ackermann M, Lutz TA, Reusch CE.
Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell
loss in the domestic cat.
Diabetologia.
2009;
52
336-346
MissingFormLabel
- 21
Appleton DJ, Rand JS, Sunvold GD.
Basal plasma insulin and homeostasis model assessment (HOMA) are indicators of insulin
sensitivity in cats.
J Feline Med Surg.
2005;
7
183-193
MissingFormLabel
- 22
Matsuda M, DeFronzo RA.
Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison
with the euglycemic insulin clamp.
Diabetes Care.
1999;
22
1462-1470
MissingFormLabel
- 23
Zini E, Linscheid P, Franchini M, Kaufmann K, Monnais E, Kutter AP, Ackermann M, Lutz TA, Reusch CE.
Partial sequencing and expression of genes involved in glucose metabolism in adipose
tissues and skeletal muscle of healthy cats.
Vet J.
2009;
180
66-70
MissingFormLabel
- 24
Kipar A, Leutenegger CM, Hetzel U, Akens MK, Mislin CN, Reinacher M, Lutz H.
Cytokine mRNA levels in isolated feline monocytes.
Vet Immunol Immunopathol.
2001;
78
305-315
MissingFormLabel
- 25 Lane DJ. 16S/23S rRNA sequencing.. In: Stackebrandt E, and, Goodfellow M, (ed). Nucleic acids techniques in bacterial systematics. Chichester, United Kingdom: John Wiley & Sons; 1991: 115-147
MissingFormLabel
- 26
Storgaard H, Jensen CB, Björnholm M, Song XM, Madsbad S, Zierath JR, Vaag AA.
Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling
in skeletal muscle in men at risk for type 2 diabetes.
J Clin Endocrinol Metab.
2004;
89
1301-1311
MissingFormLabel
- 27
Salomaa V, Ahola I, Tuomilehto J, Aro A, Pietinen P, Korhonen HJ, Penttilä I.
Fatty acid composition of serum cholesterol esters in different degrees of glucose
intolerance: a population-based study.
Metabolism.
1990;
39
1285-1291
MissingFormLabel
- 28
Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV.
The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle
phospholipids.
N Engl J Med.
1993;
328
238-244
MissingFormLabel
- 29
Vessby B, Tengblad S, Lithell H.
Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal
muscle phospholipids in 70-year-old men.
Diabetologia.
1994;
37
1044-1050
MissingFormLabel
- 30
Lovejoy JC, Smith SR, Champagne CM, Most MM, Lefevre M, DeLany JP, Denkins YM, Rood JC, Veldhuis J, Bray GA.
Effects of diets enriched in saturated (palmitic), monounsaturated (oleic), or trans
(elaidic) fatty acids on insulin sensitivity and substrate oxidation in healthy adults.
Diabetes Care.
2002;
25
1283-1288
MissingFormLabel
- 31
Noto A, Zahradka P, Yurkova N, Xie X, Truong H, Nitschmann E, Ogborn MR, Taylor CG.
Dietary conjugated linoleic acid decreases adipocyte size and favorably modifies adipokine
status and insulin sensitivity in obese, insulin-resistant rats.
Metabolism.
2007;
56
1601-1611
MissingFormLabel
- 32
Ceron JJ, Eckersall PD, Martýnez-Subiela S.
Acute phase proteins in dogs and cats: current knowledge and future perspectives.
Vet Clin Pathol.
2005;
34
85-99
MissingFormLabel
- 33
Skurk T, Alberti-Huber C, Herder C, Hauner H.
Relationship between adipocyte size and adipokine expression and secretion.
J Clin Endocrinol Metab.
2007;
92
1023-1033
MissingFormLabel
- 34
Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE.
Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type
II diabetes independent of insulin resistance.
Diabetologia.
2000;
43
1498-1506
MissingFormLabel
- 35
Wueest S, Rapold RA, Rytka JM, Schoenle EJ, Konrad D.
Basal lipolysis, not the degree of insulin resistance, differentiates large from small
isolated adipocytes in high-fat fed mice.
Diabetologia.
2009;
52
541-546
MissingFormLabel
- 36
Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE.
Increased hepatic and circulating interleukin-6 levels in human non-alcoholic steatohepatitis.
Am J Gastroenterol.
2008;
103
1372-1379
MissingFormLabel
- 37
Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T.
Measurement of the high-molecular weight form of adiponectin in plasma is useful for
the prediction of insulin resistance and metabolic syndrome.
Diabetes Care.
2006;
29
1357-1362
MissingFormLabel
- 38
Hoenig M, Thomaseth K, Waldron M, Ferguson DC.
Insulin sensitivity, fat distribution, and adipocytokine response to different diets
in lean and obese cats before and after weight loss.
Am J Physiol Regul Integr Comp Physiol.
2007;
292
R227-R234
MissingFormLabel
- 39
Trevaskis JL, Gawronska-Kozak B, Sutton GM, McNeil M, Stephens JM, Smith SR, Butler AA.
Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout
mice.
Obesity.
2007;
15
2664-2672
MissingFormLabel
- 40
Ajuwon KM, Spurlock ME.
Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases
PPARgamma2 expression in adipocytes.
Am J Physiol Regul Integr Comp Physiol.
2005;
288
R1220-R1225
MissingFormLabel
- 41
Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies Y, Ludgate M, Rossetti L, Scherer PE.
A transgenic mouse with a deletion in the collagenous domain of adiponectin displays
elevated circulating adiponectin and improved insulin sensitivity.
Endocrinology.
2004;
145
367-383
MissingFormLabel
- 42
Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ.
Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular
domain of adiponectin in primary rat adipocytes.
Diabetes.
2003;
52
1355-1363
MissingFormLabel
Correspondence
E. Zini
Clinic for Small Animal Internal Medicine
Vetsuisse Faculty
University of Zürich
Winterthurerstraße 260
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Email: ezini@vetclinics.uzh.ch