| 1. |
- Eriksson, Jan W., et al.
(författare)
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Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation : the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study
- 2008
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Ingår i: Hypertension. - : American Heart Association. - 0194-911X .- 1524-4563. ; 52:6, s. 1030-1037
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P
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| 2. |
- Boesgaard, T. W., et al.
(författare)
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The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:5, s. 816-20
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients. METHODS: We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/INTERPRETATION: Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
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| 3. |
- Boesgaard, T. W., et al.
(författare)
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Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study
- 2009
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Ingår i: PLoS One. - 1932-6203. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKROUND: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. METHODOLOGY/RESULTS: Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. CONCLUSION: The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.
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| 4. |
- Brekke, Hilde Kristin, 1972, et al.
(författare)
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Lifestyle modification improves risk factors in type 2 diabetes relatives.
- 2005
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Ingår i: Diabetes research and clinical practice. - : Elsevier BV. - 0168-8227. ; 68:1, s. 18-28
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate the short-term (16 weeks) effect of lifestyle intervention on insulin sensitivity, anthropometric and metabolic variables in non-diabetic first-degree relatives of type 2 diabetic patients (FDR). METHODS: Seventy-seven (49 male, 28 female) FDR were allocated to one of three groups, diet (D-group; n = 25), diet and exercise (DE-group; n = 30) or control group (C-group; n = 22). Lifestyle counselling was based on current nutrition recommendations, including increased intake of fatty fish and low glycaemic index foods. Group counselling was given on two occasions with follow-up through telephone interviews every 10 days. Assessments included insulin sensitivity index (Si), anthropometry, lipid parameters, circulating leptin and adiponectin levels. RESULTS: The D-group reduced total cholesterol (-0.31 mmol/l, P = 0.024), LDL cholesterol (-0.22 mmol/l, P = 0.021) and apolipoprotein B (-9.5 mg/dl, P = 0.009) levels, whereas the DE-group decreased body weight (-2.1%, P = 0.030) and waist circumference (-3.0 cm, P < 0.001) versus controls. A 13% reduction in fasting insulin was observed in the DE-group, but no significant improvement in Si in D-group or DE-group was observed. A subgroup, adherent to diet and who increased exercise, significantly improved Si and lipid profile. CONCLUSIONS: The improved metabolic risk profile in FDR suggests that lifestyle changes can be effective in individuals at high risk to develop type 2 diabetes and cardiovascular disease.
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| 5. |
- Brekke, Hilde Kristin, 1972, et al.
(författare)
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Long-term (1- and 2-year) effects of lifestyle intervention in type 2 diabetes relatives.
- 2005
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Ingår i: Diabetes research and clinical practice. - : Elsevier BV. - 0168-8227. ; 70:3, s. 225-34
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To study the long-term (1- and 2-year) effect of a lifestyle intervention on non-diabetic first-degree relatives of type 2 diabetic patients, i.e., the 1-year effect of diet versus diet and exercise in relation to a control group and the 2-year sustainability of these treatment effects. METHOD: Seventy-seven healthy first-degree relatives (men and women) between the ages of 25 and 55 were allocated to one of three groups: diet group (D), diet and exercise group (DE) and control group (C). For ethical reasons, after 1 year the control group began the intervention and were followed for another 2 years. Diet and physical activity counselling was based on current nutrition recommendations, including increased intake of fatty fish and low glycaemic index foods. The fatty acid composition of the erythrocyte membrane was studied as an objective measure of dietary change. Assessments included fasting insulin, 2-h insulin, oral glucose tolerance test (OGTT), anthropometry and blood lipid measurements. Groups D and DE received intensive follow-up through unannounced telephone interviews during the first 4 months. RESULTS: Dietary changes were significant at 1 year, and to a large degree sustained at 2 years. Adherence to advice regarding fat quality was confirmed through changes in the fatty acid composition of the erythrocyte membrane. The least active subjects in DE increased their physical activity (PA). At 1 year, group D showed a reduction in the ratio of LDL to HDL cholesterol (p=0.028) while group DE decreased their body weight by 2.7% (p<0.029) and increased HDL (p<0.037) versus controls. At 2 years, cholesterol levels (total, LDL and the ratio LDL/HDL) were reduced within group D and when compared to DE (p=0.022, 0.009, 0.035, respectively). Fasting insulin was reduced within group DE and when compared to group D (p=0.025). CONCLUSIONS: Positive changes in lifestyle, blood lipids and fasting insulin can be achieved and maintained in a non-diabetic population at risk of type 2 diabetes after 2 years.
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| 6. |
- Dahlgren, Eva, et al.
(författare)
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Sertoli-Leydig cell tumour in a postmenopausal woman showing all facets of the insulin resistance syndrome (IRS)
- 2005
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Ingår i: Ups J Med Sci. - 0300-9734. ; 110:3, s. 233-6
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Tidskriftsartikel (refereegranskat)abstract
- Sertoli-Leydig cell tumours are rare sex stromal tumours with an incidence of < 0.5% of all ovarian tumours. Most frequently this tumour occurs in young women with a history of amenorrhoea, hirsutism and lowered pitch. Here, we report on a woman with IRS, postmenopausal virilization and increased testosterone levels due to a Sertoli-Leydig cell tumour. This is the first case to suggest an association between IRS and Sertoli-Leydig cell tumours. Furthermore, we highlight the difficulties in detecting this ovarian tumour with sonography.
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| 7. |
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| 8. |
- Gogg, Silvia, 1962, et al.
(författare)
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Increased MAPK activation and impaired insulin signaling in subcutaneous microvascular endothelial cells in type 2 diabetes: the role of endothelin-1
- 2009
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Ingår i: Diabetes. - 1939-327X. ; 58:10, s. 2238-45
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To establish a method for isolation and culture of subcutaneous microvascular endothelial cells (MVEC) from small human tissue biopsies to compare gene and protein expression of insulin signaling molecules in MVEC from insulin-resistant and healthy control subjects. RESEARCH DESIGN AND METHODS: Stromavascular cells from subcutaneous needle biopsies of type 2 diabetic and control subjects were expanded in culture and the endothelial cells selected with magnetic immune separation. Western blots and RT-PCR were used for protein and gene expression assays. RESULTS: At least 99% of the expanded primary MVEC could be characterized as endothelial cells. The expression of insulin receptors was low, but insulin increased tyrosine phosphorylation of both the insulin receptor and insulin receptor substrate (IRS)-1 and activated protein kinase B (PKB). The IRS-1 protein expression was reduced and the serine phosphorylation of PKB in response to insulin attenuated whereas basal and insulin-stimulated phosphorylation of extracellular signal-related kinase (ERK)1/2 was increased in type 2 diabetes MVEC. Endothelin (ET)-1 mRNA levels were significantly higher in type 2 diabetes cells. The addition of ET-1 increased the phosphorylation of mitogen-activated protein kinase (MAPK), an effect antagonized by the MEK-1 inhibitor PD98059. Furthermore, the endothelin ET(A) and ET(B) receptor antagonists BQ123 and BQ788 decreased basal MAPK activity in type 2 diabetes MVEC and prevented the ET-1-induced activation. CONCLUSIONS: We developed a system for isolation and culture of human MVEC from small needle biopsies. Our observations support the concept of "selective" insulin resistance, involving IRS-1 and the PI3kinase pathway, as an underlying factor for a dysregulated microvascular endothelium in type 2 diabetes. Our data also support a role of ET-1 for the increased MAPK activity seen in nonstimulated type 2 diabetes MVEC.
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| 9. |
- Graham, T. E., et al.
(författare)
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Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects
- 2006
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Ingår i: N Engl J Med. - 1533-4406. ; 354:24, s. 2552-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance. METHODS: We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. RESULTS: Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. CONCLUSIONS: RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
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| 10. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 48:1, s. 96-104
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined whether short-term treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPARgamma co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. METHODS: Ten non-diabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic-hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. RESULTS: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPARgamma co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-alpha increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. CONCLUSIONS/INTERPRETATION: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.
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