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Neurohormonal mechanisms in insulin resistance and type 2 diabetes
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
2004 (English)Doctoral 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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2004. , 59 p.
Identifiers
URN: urn:nbn:se:umu:diva-225ISBN: 91-7305-591-3 (print)OAI: oai:DiVA.org:umu-225DiVA: diva2:142731
Public defence
2004-04-24, 09:00
Opponent
Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2010-08-05Bibliographically approved
List of papers
1. Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients: potential role of steroid hormones and leptin in the development of insulin resistance
Open this publication in new window or tab >>Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients: potential role of steroid hormones and leptin in the development of insulin resistance
2002 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 32, no 3, 172-178 p.Article in journal (Refereed) Published
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.

Keyword
Body fat, cortisol, insulin resistance, leptin, testosterone, type 2 diabetes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3844 (URN)10.1046/j.1365-2362.2002.00963.x (DOI)11895468 (PubMedID)
Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2017-12-14Bibliographically approved
2. 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 subjects
Open this publication in new window or tab >>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 subjects
2003 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 20, no 5, 399-405 p.Article in journal (Refereed) Published
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.

Keyword
insulin sensitivity, Type 2 diabetes, autonomic nervous system, heart rate variability, spectral analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3845 (URN)10.1046/j.1464-5491.2003.00920.x (DOI)12752490 (PubMedID)
Available from: 2004-03-31 Created: 2004-03-31 Last updated: 2017-12-14Bibliographically approved
3. Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance
Open this publication in new window or tab >>Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance
Show others...
2005 (English)In: Obesity Research, ISSN 1071-7323, E-ISSN 1550-8528, Vol. 13, no 4, 717-728 p.Article in journal (Refereed) Published
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.

Keyword
Type 2 diabetes, family history, insulin resistance, cortisol axis, visceral fat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-14122 (URN)10.1038/oby.2005.81 (DOI)15897481 (PubMedID)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
4. Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo
Open this publication in new window or tab >>Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo
2006 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 3, 301-309 p.Article in journal (Refereed) Published
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.

Keyword
adipose tissue/*metabolism, adrenocorticotropic hormone/diagnostic use, analysis of variance, blood glucose/analysis, c-reactive protein/analysis, case-control studies, dexamethasone/diagnostic use, diabetes mellitus; type 2/*metabolism, fatty acids, nonesterified/blood, glucocorticoids/diagnostic use, glucose clamp technique, humans, hydrocortisone/blood, insulin resistance, interleukin-6/*metabolism, linear models, stimulation, chemical, tumor necrosis factor-alpha/*metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-15370 (URN)10.1111/j.1365-2265.2006.02593.x (DOI)16918948 (PubMedID)
Available from: 2007-07-05 Created: 2007-07-05 Last updated: 2017-12-14Bibliographically approved

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