Tissue-specific insulin sensitivity in humans - with special reference to the liver

The number of individuals affected by Type 2 diabetes mellitus (T2DM) is increasing rapidly nearly everywhere in the world. Insulin resistance, which means reduced impact of insulin in its target tissues, especially in the liver, skeletal muscle and adipose tissue, is the defining hallmark of T2DM. Insulin resistance in these tissues manifests as impaired ability to take up glucose and fatty acids from blood after a meal, increased production of glucose and triglycerides into the blood circulation by the liver and increased release of free fatty acids into the blood by adipose tissue. This thesis work focuses on studying insulin resistance using a cross-sectional cohort of a wide range of individuals of different ages and body mass index (BMI). P.Pro12Ala polymorphism of the PPARG gene reduces diabetes risk, and the aim of this study was to determine whether this variant affects liver insulin sensitivity. Further goals were to study associations between insulin sensitivity in different tissues and to develop inexpensive and fast models to identify muscle and whole-body insulin resistance. Moreover, possible benefits of resistance training to liver and adipose tissue insulin sensitivity among elderly women were evaluated. It was found that overweight and obese carriers of the p.Pro12Ala polymorphism of the PPARG gene display higher insulin-stimulated liver glucose uptake when compared to carriers of the common p.Pro12Pro genotype. It was discovered that insulin resistance is more likely to be present simultaneously in skeletal muscle and adipose tissue than in the liver, and that insulin sensitivity is affected by obesity, sex and age. The developed regression models based on serum metabolomics for identifying whole-body and skeletal muscle insulin resistance correlated with insulin sensitivity better than the currently used fasting surrogate markers for insulin resistance. Moreover, it was revealed resistance training does not affect adipose tissue glucose uptake but instead improves insulin suppression of endogenous glucose production in elderly women and may thus prevent glucose levels rising too high after a meal. In conclusion, this thesis work shows that genetic mutations can alter tissue insulin sensitivity, and insulin resistance tends to be simultaneously present in several tissues. The newly developed models for identifying insulin resistance may improve the possibility of finding persons at risk of diabetes and ultimately cardiovascular disease. In addition, resistance training is an effective tool for improving diabetes and cardiovascular disease risk factors.Insuliinin vaikutus ihmisen kudoksissa – erityisesti maksassa Tyypin 2 diabetes lisääntyy nopeasti lähes kaikkialla maailmassa. Tyypin 2 diabetekselle on tunnusomaista erityisesti lihaksessa, maksassa sekä rasvakudoksessa esiintyvä insuliiniresistenssi. Insuliiniresistenssi esiintyy näissä kudoksissa heikentyneenä kykynä ottaa sokeria ja rasvahappoja verenkierrosta aterian jälkeen. Lisäksi maksassa se esiintyy lisääntyneenä glukoosin ja triglyseridien tuottamisena ja rasvakudoksessa lisääntyneenä rasvahappojen erityksenä verenkiertoon. Tässä väitöskirjatyössä tutkittiin insuliiniresistenssin esiintymistä eri kudoksissa positroniemissiotomografiaa hyödyntäen kohortissa, jonka ikä- ja painoindeksijakauma on laaja. Työssä selvitettiin vaikuttaako diabetekselta suojaava PPARG-geenin p.Pro12Ala-alleeli maksan insuliiniherkkyyteen sekä kehitettiin yksinkertaisia malleja, joita voidaan hyödyntää koko kehon ja luurankolihaksen insuliiniresistenssin tunnistamisessa. Lisäksi tutkittiin voidaanko lihasvoimaharjoittelun avulla parantaa maksan ja rasvakudoksen insuliiniherkkyyttä iäkkäillä naisilla. Insuliiniherkkyyden geneettistä taustaa selvitettäessä havaittiin maksan glukoosinkäyttökyvyn olevan suurempi ylipainoisilla ja lihavilla PPARG-geenin p.Pro12Ala-alleelin kantajilla verrattuna p.Pro12Pro-genotyyppiä kantaviin. Työssä havaittiin lisäksi, että insuliiniresistenssi esiintyy useammin yhtäaikaisesti luurankolihaksessa ja rasvakudoksessa kuin maksassa sekä todettiin lihavuuden, sukupuolen ja iän olevan insuliiniherkkyyteen vaikuttavia tekijöitä. Työssä koko kehon ja luurankolihaksen insuliiniherkkyyden mittaamiseksi luodut metabolomiikkaan perustuvat mallit ovat tarkempia, kuin tällä hetkellä suurissa kliinisissä tutkimuksissa käytössä olevat insuliiniherkkyyttä mittaavat epäsuorat indeksit. Lihasvoimaharjoittelua käsittelevässä työssä havaittiin, että harjoittelu ei vaikuta rasvakudoksen insuliiniherkkyyteen, mutta parantaa insuliinin kykyä vähentää maksan glukoosintuotantoa iäkkäillä naisilla, mikä puolestaan voi ehkäistä verensokerin kohoamista. Tässä työssä osoitettiin, että p.Pro12Ala polymorfia parantaa maksan insuliiniherkkyyttä ja insuliiniresistenssi esiintyy usein useissa kudoksissa yhtäaikaisesti. Työssä kehitettiin lupaavia malleja insuliiniresistenssin tunnistamiseen, jotka saattavat auttaa löytämään henkilöitä, joilla on kohonnut riski tyypin 2 diabeteksen ja lopulta sydän- ja verenkiertosairauksien kehittymiseen. Lisäksi työssä näytettiin, kuinka tyypin 2 diabeteksen ja sydän- ja verisuonitautien riskitekijöitä voidaan vähentää voimaharjoittelun avulla

Hepatic Positron Emission Tomography: Applications in Metabolism, Haemodynamics and Cancer

Evaluating in vivo the metabolic rates of the human liver has been a challenge due to its unique perfusion system. Positron emission tomography (PET) represents the current gold standard for assessing non-invasively tissue metabolic rates in vivo. Here, we review the existing literature on the assessment of hepatic metabolism, haemodynamics and cancer with PET. The tracer mainly used in metabolic studies has been [F-18]2-fluoro-2-deoxy-D-glucose (F-18-FDG). Its application not only enables the evaluation of hepatic glucose uptake in a variety of metabolic conditions and interventions, but based on the kinetics of F-18-FDG, endogenous glucose production can also be assessed. 14(R,S)-[F-18]fluoro-6-thia-Heptadecanoic acid (F-18-FTHA), C-11-Palmitate and C-11-Acetate have also been applied for the assessment of hepatic fatty acid uptake rates (F-18-FTHA and C-11-Palmitate) and blood flow and oxidation (C-11-Acetate). Oxygen-15 labelled water (O-15-H2O) has been used for the quantification of hepatic perfusion. F-18-FDG is also the most common tracer used for hepatic cancer diagnostics, whereas C-11-Acetate has also shown some promising applications in imaging liver malignancies. The modelling approaches used to analyse PET data and also the challenges in utilizing PET in the assessment of hepatic metabolism are presented

Pleiotropic Effects of Secretin: A Potential Drug Candidate in the Treatment of Obesity?

Secretin is the first hormone that has been discovered, inaugurating the era and the field of endocrinology. Despite the initial focus, the interest in its actions faded away over the decades. However, there is mounting evidence regarding the pleiotropic beneficial effects of secretin on whole-body homeostasis. In this review, we discuss the evidence from preclinical and clinical studies based on which secretin may have a role in the treatment of obesity.</p

Circulating Docosahexaenoic Acid Associates with Insulin-Dependent Skeletal Muscle and Whole Body Glucose Uptake in OlderWomen Born from Normal Weight Mothers

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. The circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: Thirty-seven elderly women were separated into elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using proton nuclear magnetic resonance (1H-NMR) and insulin-dependent tissue-specific glucose uptake in skeletal muscle was assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the docosahexaenoic acid percentage of the total long-chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (p = 0.015). DHA/FA associated significantly with skeletal muscle glucose uptake (GU) (p = 0.031) and the metabolizable glucose value derived from hyperinsulinemic-euglycemic clamp technique (M-value) in the OLM group only (p = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and this association is significantly weakened in the offspring of obese mothers.Peer reviewe

Circulating Docosahexaenoic Acid Associates with Insulin-Dependent Skeletal Muscle and Whole Body Glucose Uptake in OlderWomen Born from Normal Weight Mothers

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. The circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: Thirty-seven elderly women were separated into elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using proton nuclear magnetic resonance (1H-NMR) and insulin-dependent tissue-specific glucose uptake in skeletal muscle was assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the docosahexaenoic acid percentage of the total long-chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (p = 0.015). DHA/FA associated significantly with skeletal muscle glucose uptake (GU) (p = 0.031) and the metabolizable glucose value derived from hyperinsulinemic-euglycemic clamp technique (M-value) in the OLM group only (p = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and this association is significantly weakened in the offspring of obese mothers

Insulin-stimulated glucose uptake in skeletal muscle, adipose tissue and liver: A positron emission tomography study

Objective: Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific. Design and methods: We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic–hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort. Results: Skeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging. Conclusions: We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.</p

Diagnostic Accuracy of F-18-FDG-PET/CT and F-18-FDG-PET/MRI in Detecting Locoregional Recurrence of HNSCC 12 Weeks after the End of Chemoradiotherapy: Single-Center Experience with PET/MRI

PurposeIn head and neck squamous cell carcinoma (HNSCC), the early diagnosis and efficient detection of recurrences and/or residual tumor after treatment play a very important role in patient's prognosis. Positron emission tomography (PET) using 2-deoxy-2-F-18-fluoro-D-glucose (F-18-FDG) has become an established method for the diagnosis of suspected recurrence in head and neck carcinomas. In particular, integrated PET/MRI imaging that provides optimal soft tissue contrast and less dental implant artifacts compared to PET/CT is an intriguing technique for the follow-up imaging of HNSCC patients. The aim of this study was to evaluate the benefit of PET/MRI compared to PET/CT in post-treatment follow-up imaging of HNSCC patients.MethodsThis retrospective observational cohort study consists of 104 patients from our center with histologically confirmed HNSCC. All patients received chemoradiotherapy (CRT) and underwent F-18-FDG-PET/CT (n=52) or F-18-FDG-PET/MRI (n=52) scan 12 weeks after the end of treatment. Image analysis was performed by two independent readers according to a five-point Likert scale analysis. ResultsPET/MRI was more sensitive (1.00 vs. 0.77) than PET/CT in the detection of locoregional recurrence. PET/MRI also had better negative (1.00 vs. 0.87) predictive values. AUCs for PET/MRI and PET/CT on patient-based analysis were 0.997 (95% CI 0.989-1.000) and 0.890 (95% CI 0.806-0.974), respectively. The comparison of sensitivity, AUCs, and negative predictive values revealed a statistically significant difference, pConclusionBased on these results, PET/MRI might be considered the modality of choice in detecting locoregional recurrence in HNSCC patients, especially in the more advanced stages in the oral cavity, larynx, or nasopharynx.</p

The Obesity Risk SNP (rs17782313) near the MC4R Gene Is Not Associated with Brain Glucose Uptake during Insulin Clamp-A Study in Finns

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [F-18]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance

Brain glucose uptake is associated with endogenous glucose production in obese patients before and after bariatric surgery and predicts metabolic outcome at follow-up

Aims: To investigate further the finding that insulin enhances brain glucose uptake (BGU) in obese but not in lean people by combining BGU with measures of endogenous glucose production (EGP), and to explore the associations between insulin-stimulated BGU and peripheral markers, such as metabolites and inflammatory markers. Materials and methods: A total of 20 morbidly obese individuals and 12 lean controls were recruited from the larger randomized controlled SLEEVEPASS study. All participants were studied under fasting and euglycaemic hyperinsulinaemic conditions using fluorodeoxyglucose-positron emission tomography. Obese participants were re-evaluated 6 months after bariatric surgery and were followed-up for ~3 years. Results: In obese participants, we found a positive association between BGU and EGP during insulin stimulation. Across all participants, insulin-stimulated BGU was associated positively with systemic inflammatory markers and plasma levels of leucine and phenylalanine. Six months after bariatric surgery, the obese participants had achieved significant weight loss. Although insulin-stimulated BGU was decreased postoperatively, the association between BGU and EGP during insulin stimulation persisted. Moreover, high insulin-stimulated BGU at baseline predicted smaller improvement in fasting plasma glucose at 2 and 3 years of follow-up. Conclusions: Our findings suggest the presence of a brain-liver axis in morbidly obese individuals, which persists postoperatively. This axis might contribute to further deterioration of glucose homeostasis.</p

Renal Sinus Fat Is Expanded in Patients with Obesity and/or Hypertension and Reduced by Bariatric Surgery Associated with Hypertension Remission

Renal sinus fat is a fat depot at the renal hilum. Because of its location around the renal artery, vein, and lymphatic vessels, an expanded renal sinus fat mass may have hemodynamic and renal implications. We studied whether renal sinus fat area (RSF) associates with hypertension and whether following bariatric surgery a decrease in RSF associates with improvement of hypertension. A total of 74 severely obese and 46 lean controls were studied with whole-body magnetic resonance imaging (MRI). A total of 42 obese subjects were re-studied six months after bariatric surgery. RSF was assessed by two independent researchers using sliceOmatic. Glomerular filtration rate (eGFR) was estimated according to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Patients with obesity accumulated more RSF compared to lean controls (2.3 [1.7-3.1] vs. 1.8 [1.4-2.5] cm(2), p = 0.03). Patients with hypertension (N = 36) had a larger RSF depot compared to normotensive subjects (2.6 [2.0-3.3] vs. 2.0 [1.4-2.5] cm(2), p = 0.0007) also after accounting for body mass index (BMI). In the pooled data, RSF was negatively associated with eGFR (r = -0.20, p = 0.03), whereas there was no association with systolic or diastolic blood pressure. Following bariatric surgery, RSF was reduced (1.6 [1.3-2.3] vs. 2.3 [1.7-3.1] cm(2), p = 0.03) along with other markers of adiposity. A total of 9/27 of patients achieved remission from hypertension. The remission was associated with a larger decrease in RSF, compared to patients who remained hypertensive (-0.68 [ -0.74 to -0.44] vs. -0.28 [ -0.59 to 0] cm(2), p = 0.009). The accumulation of RSF seems to be involved in the pathogenesis of hypertension in obesity. Following bariatric surgery, loss of RSF was associated with remission from hypertension