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- Hellebö Johanson, Else, 1969, et al.
(författare)
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No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes
- 2005
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Ingår i: Diabetes Metab Res Rev. - : Wiley. - 1520-7552. ; 21:4, s. 376-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To study the acute effect of nateglinide, an insulinotropic agent, on the postprandial triglyceride and lipoprotein responses in subjects at risk for type 2 diabetes. METHODS: Six women and 10 men, with at least one first-degree relative with type 2 diabetes were included (Age: 48 +/- 7 years, BMI: 27.5 +/- 2.8 kg m(-2), P-triglycerides: 1.3 +/- 0.4 mmol L(-1), P-cholesterol: 5.4 +/- 0.6 mmol L(-1), B-glucose: 4.6 +/- 0.3 mmol L(-1)). They each had two 8-h meal tolerance tests with either nateglinide or placebo given 10 min prior to the meals in randomized order. Lipoprotein fractions were separated by density gradient ultracentrifugation. First-phase insulin secretion was assessed by an intravenous glucose tolerance test (300 mg kg(-1) body weight) and insulin sensitivity by a hyperinsulinaemic euglycaemic clamp (40 mU m(-2) min(-1)). RESULTS: The 1-h insulin levels during the meal tolerance test were significantly higher with nateglinide (577 +/- 81 vs 376 +/- 58 pmol L(-1), p < 0.001), as well as the response during the first two hours (IAUC: 41 243 +/- 5844 vs 29 956 +/- 4662 pmol L(-1) min, p < 0.01). Accordingly, nateglinide lowered the 8-h postprandial glucose response by around 60% compared to placebo (p < 0.001). In contrast, no significant lowering was seen in the excursion of postprandial triglycerides in total plasma or lipoprotein fractions. Consistently, the concentration of exogenous (apoB-48) and endogenous (apoB-100) lipoproteins was not reduced by nateglinide. CONCLUSIONS: Acute administration of nateglinide reduces, as expected, the postprandial glucose concentration, but no reduction in triglyceride or lipoprotein responses are seen in subjects at risk for type 2 diabetes.
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| 2. |
- Murdolo, Giuseppe, 1966, et al.
(författare)
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Monocyte chemoattractant protein-1 in subcutaneous abdominal adipose tissue: characterization of interstitial concentration and regulation of gene expression by insulin
- 2007
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Ingår i: J Clin Endocrinol Metab. - : The Endocrine Society. - 0021-972X. ; 92:7, s. 2688-95
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in obesity-associated chronic inflammation, insulin resistance, and atherosclerosis. OBJECTIVES: The objectives of this study were to: 1) characterize the interstitial levels and the gene expression of MCP-1 in the sc abdominal adipose tissue (SCAAT), 2) elucidate the response of MCP-1 to acute hyperinsulinemia, and 3) determine the relationship between MCP-1 and arterial stiffness. DESIGN: Nine lean (L) and nine uncomplicated obese (OB) males were studied in the fasting state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Interstitial and serum MCP-1 (iMCP-1 and sMCP-1, respectively) levels, pulse wave analysis, and SCAAT biopsies were characterized at baseline and after hyperinsulinemia. RESULTS: OB showed elevated sMCP-1 (P < 0.01) but similar iMCP-1 levels as compared with L. Basal iMCP-1 concentrations were considerably higher than sMCP-1 (P < 0.0001), and a gradient between iMCP-1 and sMCP-1 levels was maintained throughout the hyperinsulinemia. At baseline, SCAAT gene expression profile revealed a "co-upregulation" of MCP-1, MCP-2, macrophage inflammatory protein-1alpha, and CD68 in OB, and whole-body glucose disposal inversely correlated with the MCP-1 gene expression. After hyperinsulinemia, MCP-1 and MCP-2 mRNA levels significantly increased in L, but not in OB. Finally, sMCP-1 excess in the OB positively correlated with the stiffer vasculature. CONCLUSIONS: These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals. In human obesity, we suggest the SCAAT MCP-1 gene overexpression as a biomarker of an "inflamed" adipose organ and impaired glucose metabolism.
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| 3. |
- Sandqvist, Madelene, 1974, et al.
(författare)
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Low adipocyte IRS-1 protein expression is associated with an increased arterial stiffness in non-diabetic males
- 2005
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 180:1, s. 119-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Low adipocyte IRS-1 protein expression is a biomarker for insulin resistance and early atherosclerosis. However, whether IRS-1 protein expression is related to systemic arterial stiffness, is unknown. METHODS AND RESULTS: Ten non-diabetic male subjects with low adipocyte IRS-1 protein expression (LIRS) were matched with 10 non-diabetic males with normal IRS-1 protein expression (NIRS). Augmentation index (AIx) and time for reflection of pulse wave (Tr) were studied with pulse wave analysis, both in the fasting state and during a euglycemic hyperinsulinemic clamp. The LIRS-group showed an increased fasting insulin concentration (fP-insulin 71+/-4 pmol/L versus 58+/-5 pmol/L; p=0.02 (mean+/-S.E.)), whereas glucose disposal rate during the clamp (8.7+/-0.8 mg/kg LBM/min versus 10.3+/-1.3 mg/kg LBM/min; n.s.) did not differ significantly. Blood pressure, lipid parameters, adiponectin, endothelin-1 and CRP concentrations were similar. However, in the basal state, AIx was increased (129+/-4% versus 116+/-2%; p<0.02) and Tr was decreased (150+/-3 ms versus 171+/-5 ms; p<0.01), suggesting stiffer vessels in the LIRS-group. The LIRS-group exhibited an attenuated AIx response to hyperinsulinemia compared to the NIRS-group. CONCLUSIONS: The data suggest that non-obese non-diabetic men with a low adipocyte IRS-1 protein expression have an increased systemic arterial stiffness.
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| 4. |
- Sandqvist, Madelene, 1974, et al.
(författare)
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Postprandial interstitial insulin concentrations in type 2 diabetes relatives
- 2006
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Ingår i: Eur J Clin Invest. - : Wiley. - 0014-2972 .- 1365-2362. ; 36:6, s. 383-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue. SUBJECTS AND METHODS: Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively. RESULTS: The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide. CONCLUSIONS: Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.
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| 5. |
- Sandqvist, Madelene, 1974
(författare)
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Studies of the adipose tissue in insulin resistance with microdialysis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes is characterized by a combination of insulin resistance and an impaired insulin secretion. Theprevalence of the disease has taken epidemic proportions, and it is therefore of great concern to characterize itspathophysiology, as well as to identify individuals with increased risk for the disease, enabling to take measuresfor prevention and cure. In the present thesis early perturbations in the abdominal adipose tissue metabolism inthe development of type 2 diabetes are characterized. Furthermore, a possible link between adipose tissuedysfunction and a risk marker for cardiovascular disease is studied.To identify early metabolic perturbations, healthy volunteers with known increased risk of developing type 2diabetes, as subjects with heredity for the disease, subjects with increased fat cell size, or subjects with a defectin the adipocyte insulin signalling system (low IRS-1 protein expression) are studied. The microdialysistechnique allows measurements of substances in the subcutaneous interstitial fluid in vivo. 133Xenon-clearancetechnique is applied for adipose tissue blood flow measurements. Subcutaneous needle biopsy is performed toallow measurement of IRS-1 protein expression by immunoblotting and measurement of fat cell size. Arterialstiffness is measured by pulse wave analysis. The euglycemic hyperinsulinemic clamp method is applied formeasurement of insulin sensitivity.In paper I the lactate release per fat cell is shown to be increased during hyperinsulinemia in subjects prone todevelop type 2 diabetes, indicating a disturbance in glucose metabolism in their subcutaneous adipocytes. Anincreased fat cell size is shown to be associated with an increased interstitial lactate concentration. In paper II anincreased fat cell size is shown to be associated with increased subcutaneous interstitial interleukin-6 (IL-6)levels in vivo, as well as increased IL-6 mRNA expression and IL-6 secretion in vitro. Increased IL-6 levels areshown to down regulate adipocyte differentiation markers in vitro, which may result in an increased fat cell size.In paper III the kinetics of transendothelial insulin transport to the adipose tissue is studied in subjects withheredity for type 2 diabetes and a decreased insulin sensitivity. The proportion of insulin passing the capillaryendothelium to the interstitium is similar at two different concentrations of physiological hyperinsulinemia,indicating that insulin action in vivo is primarily dependent on the cellular insulin sensitivity. In paper IVsubjects with a low IRS-1 protein expression in the adipocytes are shown to have an increased arterial stiffness,indicating low IRS-1 protein expression as a potential risk marker for cardiovascular disease.In conclusion, subjects prone to develop type 2 diabetes exhibit increased lactate and IL-6 levels in thesubcutaneous adipose tissue. However, the transcapillary insulin transport in the adipose tissue does not seem tobe a cause of insulin resistance in these subjects. Furthermore, an impairment in the insulin signalling cascade inthe adipocytes is identified as a risk marker for arterial stiffness.
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