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  • 1.
    Burén, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindmark, Stina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, Jan W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo?2002In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 52, no 2, p. 239-245Article in journal (Refereed)
    Abstract [en]

    Chronic hyperglycemia promotes the development of insulin resistance. The aim of this study was to investigate whether cellular insulin resistance is secondary to the diabetic state in human type 2 diabetes. Subcutaneous fat biopsies were taken from 3 age-, sex-, and body mass index (BMI)-matched groups with 10 subjects in each group: type 2 diabetes patients with either good (hemoglobin A1c [HbA1c] [lt ] 7%, G) or poor (HbA1c [gt ] 7.5%, P) metabolic control and healthy control subjects (C). Insulin action in vitro was studied by measurements of glucose uptake both directly after cell isolation and following a 24-hour incubation at a physiological glucose level (6 mmol/L). The relationship with insulin action in vivo was addressed by employing the euglycemic clamp technique. Freshly isolated fat cells from type 2 diabetes patients with poor metabolic control had [sim ]55% lower maximal insulin response (1,000 [mu ]U/mL) on glucose uptake (P [lt ] .05) compared to C. Cells from P were more insulin-resistant (P [lt ] .05) than cells from G at a low (5 [mu ]U/mL) but not at a high (1,000 [mu ]U/mL) insulin concentration, suggesting insulin insensitivity. However, following 24 hours of incubation at physiological glucose levels, insulin resistance was completely reversed in the diabetes cells and no differences in insulin-stimulated glucose uptake were found among the 3 groups. Insulin sensitivity in vivo assessed with hyperinsulinemic, euglycemic clamp (M-value) was significantly associated with insulin action on glucose uptake in fresh adipocytes in vitro (r = 0.50, P [lt ] .01). Fasting blood glucose at the time of biopsy and HbA1c, but not serum insulin, were negatively correlated to insulin's effect to stimulate glucose uptake in vitro (r = [minus ]0.36, P = .064 and r = [minus ] 0.41, P [lt ].05, respectively) in all groups taken together. In the in vivo situation, fasting blood glucose, HbA1c, and serum insulin were all negatively correlated to insulin sensitivity (M-value; r = [minus ]0.62, P[lt ] .001, r= [minus ]0.61, P[lt ] .001, and r = [minus ]0.56, p [lt ] .01, respectively). Cell size, waist-to-hip ration (WHR), and BMI correlated negatively with insulin's effect to stimulate glucose uptake both in vitro (r = [minus ]0.55, P [lt ] .01, r = [minus ]0.54, P [lt ] .01, and r = [minus ]0.43, P [lt ] .05, respectively) and in vivo (r = [minus ]0.43, P [lt ] .05, r = [minus ]0.50, P [lt ] .01, and r = [minus ]0.36, P [lt ] .05, respectively). Multiple regression analyses revealed that adipocyte cell size and WHR independently predicted insulin resistance in vitro. Furthermore, insulin sensitivity in vivo could be predicted by fasting blood glucose and serum insulin levels. We conclude that insulin resistance in fat cells from type 2 diabetes patients is fully reversible following incubation at physiological glucose concentrations. Thus, cellular insulin resistance may be mainly secondary to the hyperglycemic state in vivo.

  • 2. Jansson, PA
    et al.
    Eliasson, B
    Lindmark, Stina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, JW
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients: potential role of steroid hormones and leptin in the development of insulin resistance2002In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 32, no 3, p. 172-178Article in journal (Refereed)
    Abstract [en]

    BackgroundFirst-degree relatives of type 2 diabetes patients are at risk of developing diabetes and they display several metabolic and hormonal perturbations. The interplay between insulin resistance, steroid hormones and circulating leptin is, however, still not fully explored in this group.

    DesignThirty-three healthy first-degree relatives of type 2 diabetic patients (relatives; M/F 19/14) were compared to 33 healthy subjects without a family history of diabetes (controls) and the groups were matched for gender, age and body mass index (BMI). We performed euglycaemic hyperinsulinaemic clamps and blood was sampled for hormone analyses.

    ResultsRelatives exhibited decreased insulin sensitivity (index of metabolic clearance rate of glucose; MCRI) but when genders were analysed separately, this difference was significant only in males (11·3 ± 1·3 vs. 15·0 ± 1·5 units, means ± SEM, P = 0·030). In male relatives morning cortisol and testosterone levels were lower, whereas leptin was higher than in male controls (P = 0·018, 0·008 and 0·063, respectively). In male relatives plasma testosterone levels were significantly associated with insulin sensitivity (r = 0·48, P = 0·040). Circulating leptin levels were inversely correlated with insulin sensitivity in all subject groups (r-values –0·49 to –0·66; P < 0·05, except in female control subjects P = 0·063). These associations were present also when age and BMI or waist : hip ratio were included in stepwise multiple regression analyses.

    ConclusionMale subjects genetically predisposed for type 2 diabetes display several endocrine abnormalities including leptin, cortisol and testosterone levels. Dysregulation of these hormones may be important in the development of insulin resistance and type 2 diabetes.

  • 3.
    Lindmark, Stina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Neurohormonal mechanisms in insulin resistance and type 2 diabetes2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin resistance usually occurs early in the development of type 2 diabetes. An altered balance in the autonomic nervous system and in certain endocrine and inflammatory pathways, might contribute to the development of insulin resistance. In diabetes, hyperglycemia further aggravates insulin resistance as well as beta cell dysfunction but the mechanisms causing this phenomenon, i.e. glucotoxicity, are not fully understood.

    Insulin resistance can be demonstrated in healthy first-degree relatives of type 2 diabetes patients who also have a high risk of developing type 2 diabetes. Relatives and control subjects without family history of diabetes were studied with respect to insulin sensitivity and the activity in the autonomic nervous system (ANS) and in the cortisol axis. Levels of sex hormones, leptin and cytokines were analysed. Abdominal adipose tissue distribution was determined with computed tomography.

    Male relatives had decreased testosterone levels and increased leptin levels. There was an inverse relationship between insulin sensitivity and leptin levels, and in males a positive association between insulin sensitivity and testosterone levels. A tendency to lower parasympathetic reactivity was found in the relatives using heart rate variability assessment. The sympathetic/parasympathetic ratio during stress provocation was inversely correlated to insulin sensitivity, measured with glucose clamp. The insulin-resistant subjects also exhibited an overall blunted reactivity in the ANS. Cortisol reactivity after stimulation with ACTH and CRH was lower in the relatives. The amount of visceral adipose tissue (VAT) was associated with insulin resistance and with heart rate at rest and during controlled breathing and it also correlated with heart rate and sympathetic/parasympathetic ratio after an orthostatic manoeuvre.

    Type 2 diabetic subjects with good and poor glycemic control, respectively, and matched healthy control subjects were examined with respect to insulin sensitivity, cortisol axis activity and blood levels of leptin, sex hormones and the adipocyte-secreted inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Biopsies were taken from subcutaneous adipose tissue for determination of adipocyte size. Diabetes subjects were more insulin-resistant than controls and diabetics with poor control exhibited the highest degree of insulin resistance. This group also had the highest levels of TNF-α, morning serum cortisol and non-esterified fatty acids (NEFA). In correlation analyses, significant associations were seen between glycemic level and insulin resistance, TNF-α, IL- 6 and serum cortisol levels. Insulin resistance was positively correlated to NEFA levels, TNF-α and ACTH-stimulated cortisol levels. Adipocyte size was associated with insulin resistance and levels of IL-6 and leptin.

    The findings support a connection between insulin resistance and VAT amount, activity in the ANS and blood levels of hormones and adipocyte-derived molecules. Dysregulation in the complex interplay between such factors may contribute to the early pathogenesis of insulin resistance and type 2 diabetes. Adipokines and the cortisol system can also potentially aggravate hyperglycemia in patients with manifest type 2 diabetes.

  • 4.
    Lindmark, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, Jan W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo2006In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 3, p. 301-309Article in journal (Refereed)
    Abstract [en]

    Objective To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM). Design and methods Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed. Results Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance ( P = 0·01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes ( P = 0·05) and group P had the highest levels of fasting serum cortisol ( P = 0·05), nonesterified fatty acids (NEFA; P = 0·06) and C-reactive protein (CRP; P = 0·01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels. Conclusion Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.

  • 5.
    Lindmark, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lönn, Lars
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Tufvesson, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, Jan W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance2005In: Obesity Research, ISSN 1071-7323, E-ISSN 1550-8528, Vol. 13, no 4, p. 717-728Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the interplay among abdominal adipose tissue distribution, the cortisol axis, the autonomic nervous system, and insulin resistance. RESEARCH METHODS AND PROCEDURES: Two age-, sex-, and BMI-matched groups were studied. Fifteen subjects were first-degree relatives of patients with type 2 diabetes (R), and 15 had no family history of diabetes (controls, C). A hyperinsulinemic euglycemic clamp, cortisol measurements, and analysis of heart rate variability (HRV) were performed. Computed tomography was performed in a subgroup (n = 9 + 9) to determine abdominal adipose tissue distribution. RESULTS: R tended to be less insulin-sensitive than C (M value 9.2 +/- 1.0 vs 10.3 +/- 0.7 mg/kg per minute, not significant). Stimulation with tetracosactin or corticotropin releasing hormone yielded lower peak serum cortisol levels in R (p = 0.03 and p = 0.06, respectively). The amount of visceral abdominal fat (VAT) tended to be greater in R. In all subjects, VAT was negatively correlated to insulin sensitivity (r = -0.93, p < 0.001). There was a positive association between VAT and resting heart rate (r = 0.70, p = 0.003) and sympathetic/parasympathetic ratio in HRV assessment after tilt (r = 0.53, p = 0.03). Subcutaneous abdominal tissue was not associated with insulin sensitivity or any of the hormonal or HRV assessments. DISCUSSION: Subjects genetically predisposed for type 2 diabetes had a tendency toward a larger amount of VAT and to lower insulin sensitivity compared with control subjects. The amount of visceral fat was strongly associated with insulin resistance and signs of a high ratio of sympathetic vs. parasympathetic reactivity. A large amount of visceral fat may act in concert with sympathetic/parasympathetic imbalance to promote the development of insulin resistance, and this may be partly independent of genetic background.

  • 6.
    Lindmark, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Bjerle, P
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Eriksson, JW
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Does the autonomic nervous system play a role in the development of insulin resistance?: a study on heart rate variability in first-degree relatives of type 2 diabetes patients and control subjects2003In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 20, no 5, p. 399-405Article in journal (Refereed)
    Abstract [en]

    Aims To investigate dysregulation of the autonomic nervous system as a potential mechanism for early insulin resistance in the development of Type 2 diabetes.

    Methods Thirteen healthy individuals with first-degree relatives with Type 2 diabetes (R) were compared with 14 control subjects without family history of diabetes (C), matched for age, body mass index and sex. An oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp were performed. Analysis of heart rate variability during rest, controlled breathing, an orthostatic manoeuvre and a standardized physical stress (cold pressor test (CPT)), were used to evaluate the activity of the autonomic nervous system.

    Results Fasting blood glucose, HbA1c and serum insulin were similar in the R and C groups. The M-value, reflecting insulin sensitivity, did not differ significantly between the groups. Total spectral power and high-frequency power were lower in R during controlled breathing (P = 0.05 and P = 0.07, respectively), otherwise there were no significant differences between R and C in heart rate variability. However, low-frequency (LF)/high-frequency (HF) spectral power ratio during CPT, reflecting sympathetic/parasympathetic balance, was negatively associated with insulin sensitivity (r = −0.53, P = 0.006). When all subjects were divided into two groups by the mean M-value, the low M-value group displayed an overall higher LF/HF ratio (P = 0.04). HF power was lower in the low M-value group during controlled breathing and CPT (P = 0.01 and P = 0.03, respectively).

    Conclusion An altered balance of the parasympathetic and sympathetic nervous activity, mainly explained by an attenuated parasympathetic activity, might contribute to the development of insulin resistance and Type 2 diabetes.

  • 7.
    Lundgren, Magdalena
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Svensson, Maria
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Lindmark, Stina
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Renström, Frida
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Ruge, Toralph
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Eriksson, Jan
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Fat cell enlargement is an independent marker of insulin resistance and 'hyperleptinaemia'.2007In: Diabetologia, ISSN 0012-186X, Vol. 50, no 3, p. 625-33Article in journal (Refereed)
  • 8. Sjöstrand, M.
    et al.
    Carlson, K.
    Arnqvist, H. J.
    Gudbjörnsdottir, S.
    Landin-Olsson, M.
    Lindmark, Stina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Svensson, M. K.
    Eriksson, J. W.
    Bolinder, J.
    Assessment of beta-cell function in young patients with type 2 diabetes: arginine-stimulated insulin secretion may reflect beta-cell reserve2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 1, p. 39-48Article in journal (Refereed)
    Abstract [en]

    Objective Simple methods for the evaluation of dynamic β-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments.

    Methods Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively) were estimated. Homeostasis model assessment of β-cell function (HOMA-β) and C-peptide assessments were also used for comparisons between patients with T2D and control participants.

    Results AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (< 0.001) lower and AIRarg values were 29% (< 0.01) lower in patients with T2D compared with control participants. HOMA-β and fasting plasma C-peptide levels did not differ between the T2D and control groups.

    Conclusion In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.

  • 9. Svensson, Maria K.
    et al.
    Lindmark, Stina
    Wiklund, Urban
    Rask, Peter
    Karlsson, Marcus
    Myrin, Jan
    Kullberg, Joel
    Johansson, Lars
    Eriksson, Jan W.
    Alterations in heart rate variability during everyday life are linked to insulin resistance. A role of dominating sympathetic over parasympathetic nerve activity?2016In: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 15, article id 91Article in journal (Refereed)
    Abstract [en]

    Aims: To evaluate the role of the autonomic nervous system (ANS) in the development of insulin resistance (IR) and assess the relationship between IR and activity of ANS using power spectrum analysis of heart rate variability (HRV).

    Subjects and methods: Twenty-three healthy first-degree relatives of patients with type 2 diabetes (R) and 24 control subjects without family history of diabetes (C) group-matched for age, BMI and sex were included. Insulin sensitivity (M value) was assessed by hyperinsulinemic (56 mU/m2/min) euglycemic clamp. Activity of the ANS was assessed using power spectrum analysis of HRV in long-term recordings, i.e., 24-h ECG monitoring, and in short-term recordings during manoeuvres activating the ANS. Computed tomography was performed to estimate the amount and distribution of abdominal adipose tissue.

    Results: Insulin sensitivity (M value, mg/kg lbm/min) did not differ significantly between the R and C groups. Total spectral power (Ptot) and very low-frequency (PVLF) power was lower in R than C during 24 h ECG-recordings (p = 0.02 and p = 0.03). The best fit multiple variable linear regression model (r2 = 0.37, p < 0.001 for model) indicated that body composition (BMI) and long-term low to high frequency (LF/HF) power ratio (std β = −0.46, p = 0.001 and std β = −0.28, p = 0.003, respectively) were significantly and independently associated with the M value.

    Conclusion: Altered heart rate variability, assessed by power spectrum analysis, during everyday life is linked to insulin resistance. The data suggest that an increased ratio of sympathetic to parasympathetic nerve activity, occurring via both inherited and acquired mechanisms, could potentially contribute to the development of type 2 diabetes.

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