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1.
Nat Metab ; 5(9): 1475-1482, 2023 09.
Article de Anglais | MEDLINE | ID: mdl-37735274

RÉSUMÉ

Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2. In particular, brain insulin action increases whole-body insulin sensitivity, but these studies were mainly performed in lean men3,4. Here we investigate metabolic and hypothalamic effects of brain insulin action in women with a focus on the impact of menstrual cycle ( ClinicalTrials.gov registration: NCT03929419 ).Eleven women underwent four hyperinsulinemic-euglycemic clamps, two in the follicular phase and two in the luteal phase. Brain insulin action was introduced using nasal insulin spray5-7 and compared to placebo spray in a fourfold crossover design with change in glucose infusion rate as the primary endpoint. Here we show that during the follicular phase, more glucose has to be infused after administration of nasal insulin than after administration of placebo. This remains significant after adjustment for blood glucose and insulin. During the luteal phase, no significant influence of brain insulin action on glucose infusion rate is detected after adjustment for blood glucose and insulin (secondary endpoint). In 15 other women, hypothalamic insulin sensitivity was assessed in a within-subject design by functional magnetic resonance imaging with intranasal insulin administration8. Hypothalamus responsivity is influenced by insulin in the follicular phase but not the luteal phase.Our study therefore highlights that brain insulin action improves peripheral insulin sensitivity also in women but only during the follicular phase. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase of the menstrual cycle.


Sujet(s)
Insulinorésistance , Insuline , Mâle , Femelle , Humains , Glycémie , Encéphale , Cycle menstruel , Glucose
2.
Obesity (Silver Spring) ; 30(11): 2233-2241, 2022 11.
Article de Anglais | MEDLINE | ID: mdl-36192827

RÉSUMÉ

OBJECTIVE: Dysregulated body fat distribution is a major determinant of various diseases. In particular, increased visceral fat mass and ectopic lipids in the liver are linked to metabolic disorders such as insulin resistance and type 2 diabetes. Furthermore, interscapular fat is considered to be a metabolically active fat compartment. METHODS: This study measured interscapular fat mass and investigated its relationship with glucose metabolism in 822 individuals with a wide range of BMI values and different glucose tolerance statuses. Magnetic resonance imaging was used to quantify body fat depots, and an oral glucose tolerance test was performed to determine glucose metabolism. RESULTS: Elevated interscapular fat mass was positively associated with age, BMI, and total body, visceral, and subcutaneous adipose tissue mass. High interscapular fat mass associated with elevated fasting glucose levels, glucose levels at 2 hours during the oral glucose tolerance test, glycated hemoglobin, and insulin resistance, independent of sex, age, and total body and visceral fat mass. CONCLUSIONS: In conclusion, interscapular fat might be a highly specific fat compartment with a potential impact on glucose metabolism and the pathogenesis of diabetes mellitus.


Sujet(s)
Diabète de type 2 , Intolérance au glucose , Insulinorésistance , Humains , Intolérance au glucose/métabolisme , Graisse intra-abdominale/métabolisme , Diabète de type 2/métabolisme , Glycémie/métabolisme , Tissu adipeux/métabolisme , Insuline/métabolisme , Indice de masse corporelle
3.
Exp Clin Endocrinol Diabetes ; 130(1): 43-48, 2022 Jan.
Article de Anglais | MEDLINE | ID: mdl-32911559

RÉSUMÉ

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.


Sujet(s)
Bases de données factuelles , Complications du diabète/diagnostic , Adulte , Allemagne , Humains , Études prospectives , Plan de recherche
4.
Diabetes Care ; 45(2): 398-406, 2022 02 01.
Article de Anglais | MEDLINE | ID: mdl-34716213

RÉSUMÉ

OBJECTIVE: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.


Sujet(s)
Diabète de type 2 , Insulinorésistance , État prédiabétique , Sujet âgé , Composés benzhydryliques/pharmacologie , Diabète de type 2/traitement médicamenteux , Méthode en double aveugle , Glucosides , Humains , Hypothalamus , Adulte d'âge moyen , État prédiabétique/traitement médicamenteux
5.
Exp Clin Endocrinol Diabetes ; 130(1): 17-21, 2022 Jan.
Article de Anglais | MEDLINE | ID: mdl-34255321

RÉSUMÉ

BACKGROUND AND OBJECTIVE: This prospective, sham-controlled, randomized, cross-over study (NCT03637075), was designed to test the hypothesis that spinal cord stimulation (SCS) for the treatment of pain can also improve glucose metabolism and insulin sensitivity when compared to sham stimulation. METHODS: Ten non-diabetic participants (5 females, mean age 48.8 years) who had an SCS system implanted for the treatment of chronic neuropathic pain were studied. Whilst applying a hyperinsulinemic-euglycemic clamp, sham-stimulation and tonic stimulation were performed for 45 min (n=4) or 60 min (n=6) in each case randomly. The insulin sensitivity index and pain levels were determined. A second investigation, BurstDR stimulation was also conducted and the result was compared to that of sham stimulation (cross-over design). RESULTS: The insulin sensitivity improved significantly under the tonic stimulation when compared to the sham stimulation (p=0.037). BurstDR stimulation independently did not lead to a significantly improved insulin sensitivity compared to that after sham stimulation (p=0.16). We also examined the pain during the test and found no significant difference between sham and tonic stimulation (p=0.687). CONCLUSION: The results of this study show that tonic stimulation used for the treatment of pain could also improve glucose metabolism and insulin sensitivity. Further investigations are required to investigate the clinical relevance of the role of glucose metabolism in diabetic chronic pain participants and its underlying mechanisms.


Sujet(s)
Douleur chronique/sang , Douleur chronique/thérapie , Insulinorésistance/physiologie , Névralgie/sang , Névralgie/thérapie , Stimulation de la moelle épinière , Adulte , Études croisées , Femelle , Humains , Neurostimulateurs implantables , Mâle , Adulte d'âge moyen , Études prospectives
6.
Sci Rep ; 11(1): 20306, 2021 10 13.
Article de Anglais | MEDLINE | ID: mdl-34645853

RÉSUMÉ

Parasympathetic nervous system innervates peripheral organs including pancreas, hepatic portal system, and gastrointestinal tract. It thereby contributes to the regulation of whole-body glucose metabolism especially in the postprandial state when it promotes secretion of insulin and enhances its action in major target organs. We now aimed to evaluate the effect of parasympathetic modulation on human glucose metabolism. We used slow deep breathing maneuvers to activate the parasympathetic nervous system and tested for effects on metabolism during an oral glucose tolerance test in a randomized, controlled, cross-over trial in 15 healthy young men. We used projections towards the heart as a readout for parasympathetic activity. When analyzing heart rate variability, there was a significant increase of RMSSD (root mean square of successive differences) when participants performed slow deep breathing compared to the control condition, indicating a modulation of parasympathetic activity. However, no statistically significant effects on peripheral glucose metabolism or energy expenditure after the glucose tolerance test were detected. Of note, we detected a significant association between mean heart rate and serum insulin and C-peptide concentrations. While we did not find major effects of slow deep breathing on glucose metabolism, our correlational results suggest a link between the autonomic nervous system and insulin secretion after oral glucose intake. Future studies need to unravel involved mechanisms and develop potential novel treatment approaches for impaired insulin secretion in diabetes.


Sujet(s)
Rythme cardiaque , Respiration , Nerf vague/physiologie , Adulte , Système nerveux autonome , Glycémie/métabolisme , Peptide C/composition chimique , Études croisées , Métabolisme énergétique , Glucose/métabolisme , Hyperglycémie provoquée , Humains , Insuline/sang , Sécrétion d'insuline , Mâle , Adulte d'âge moyen , Système nerveux parasympathique/physiologie , Période post-prandiale , Fréquence respiratoire , Jeune adulte
7.
Sci Rep ; 11(1): 16642, 2021 08 17.
Article de Anglais | MEDLINE | ID: mdl-34404813

RÉSUMÉ

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body ß-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (all p ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.


Sujet(s)
Jeûne , Acide gras libre/métabolisme , Peptide gastrointestinal/métabolisme , Glicentine/métabolisme , Adulte , Poids , Calorimétrie indirecte , Femelle , Humains , Mâle , Adulte d'âge moyen , Obésité/métabolisme , Oxydoréduction
8.
J Clin Endocrinol Metab ; 106(6): 1576-1584, 2021 05 13.
Article de Anglais | MEDLINE | ID: mdl-33693827

RÉSUMÉ

CONTEXT: Pharmacological lowering of low-density lipoprotein (LDL) cholesterol potently reduces cardiovascular risk while concurrently increasing type 2 diabetes risk. OBJECTIVE: The aim of this study was to investigate the relationship between LDL cholesterol concentrations and insulin secretion and glucagon levels. METHODS: A total of 3039 individuals without cholesterol-lowering therapy, but with increased risk for diabetes, underwent routine blood tests and a 5-point oral glucose tolerance test (OGTT). Glucagon concentrations, insulin secretion, and insulin clearance indices were derived from the OGTT. RESULTS: There was no association between LDL cholesterol and fasting glucagon (P = .7, ß = -.01) or post-glucose load glucagon levels (P = .7, ß = -.07), but we detected significant positive associations of LDL cholesterol and C-peptide-based indices of insulin secretion (area under the curve [AUC]C-Peptide(0-30min)/AUCGlucose(0-30min): P < .001, ß = .06; AUCC-Peptide(0-120min) /AUCGlucose(0-120min): P < .001, ß = -.08). In contrast, we found a negative association of insulin-based insulin secretion indices with LDL concentrations (insulinogenic index: P = .01, ß = -.04; disposition index: P < .001, ß = -.06). LDL cholesterol levels, however, were positively associated with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state and post-glucose load (P < .001, ß = .09 and P < .001, ß = .06, respectively). CONCLUSION: As C-peptide based indices reflect insulin secretion independent of hepatic clearance, our results indicate lower insulin secretion in case of lesser LDL cholesterol. This could explain deteriorating glycemic control in response to cholesterol-lowering drugs.


Sujet(s)
Cholestérol LDL/métabolisme , Diabète de type 2/métabolisme , Sécrétion d'insuline/physiologie , Adulte , Glycémie/métabolisme , Cholestérol LDL/sang , Études de cohortes , Diabète de type 2/sang , Jeûne/sang , Femelle , Allemagne , Glucagon/sang , Hyperglycémie provoquée , Humains , Insuline/sang , Insulinorésistance/physiologie , Cellules à insuline/métabolisme , Mâle , Pancréas/métabolisme , Pancréas/anatomopathologie
9.
Sci Rep ; 10(1): 20466, 2020 11 24.
Article de Anglais | MEDLINE | ID: mdl-33235256

RÉSUMÉ

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.


Sujet(s)
Système nerveux autonome/métabolisme , Catécholamines/sang , Neurostimulation électrique transcutanée/méthodes , Stimulation du nerf vague/méthodes , Adulte , Études croisées , Hyperglycémie provoquée , Rythme cardiaque , Humains , Mâle , Période post-prandiale , Méthode en simple aveugle , Jeune adulte
10.
Neuroendocrinology ; 110(11-12): 929-937, 2020.
Article de Anglais | MEDLINE | ID: mdl-31689708

RÉSUMÉ

BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS: Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, ß = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, ß = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.


Sujet(s)
Hypothalamus/effets des médicaments et des substances chimiques , Hypothalamus/métabolisme , Insulinorésistance , Sécrétion d'insuline/effets des médicaments et des substances chimiques , Insuline/pharmacologie , Administration par voie nasale , Adulte , Indice de masse corporelle , Méthode en double aveugle , Humains , Insuline/administration et posologie , Imagerie par résonance magnétique , Mâle , Jeune adulte
11.
Cardiovasc Diabetol ; 18(1): 46, 2019 04 05.
Article de Anglais | MEDLINE | ID: mdl-30953516

RÉSUMÉ

BACKGROUND: SGLT2-inhibitors are potent antihyperglycemic drugs for patients with type 2 diabetes and have been shown to reduce body weight. However, it is unclear which body compartments are reduced and to what extent. METHODS: In this longitudinal observational study, we analyzed the body composition of 27 outpatients with type 2 diabetes mellitus during the first week and up to 6 months after initiation of treatment with SGLT2-inhibitors (n = 18 empagliflozin, n = 9 dapagliflozin) using bioimpedance spectroscopy (BCM, Fresenius). Fluid status of hypertensive patients taking medication with hydrochlorothiazide (n = 14) and healthy persons (n = 16) were analyzed for comparison. RESULTS: At 6 months, HbA1c decreased by 0.8% (IQR 2.3; 0.4), body weight and BMI by 2.6 kg (1.5; 9.3) and 0.9 kg/m2 (0.4; 3.3), respectively. Bioimpedance spectroscopy revealed significant decrease in adipose tissue mass and fat tissue index while lean tissue parameters remained stable. Overhydration (OH) and extracellular water (ECW) decreased by - 0.5 L/1.73 m2 (- 0.1; - 0.9) and - 0.4 L/1.73 m2 (- 0.1; - 0.8) at day 3, respectively, and returned to the initial value after 3 and 6 months. Plasma renin activity increased by 2.1-fold (0.5; 3.6) at 1 month and returned to the initial level at month 3 and 6. Fluid status of patients with SGLT2 inhibitors after 6 months showed no difference from that of hypertensive patients taking hydrochlorothiazide or healthy persons. CONCLUSIONS: Body weight reduction under the treatment with SGLT2-inhibitors is caused by reduction of adipose tissue mass and transient loss of extracellular fluid, which is accompanied by upregulation of renin-angiotensin-aldosterone system (RAAS). Permanent loss of extracellular water does not occur under SGLT2 inhibition.


Sujet(s)
Composés benzhydryliques/usage thérapeutique , Composition corporelle/effets des médicaments et des substances chimiques , Diabète de type 2/traitement médicamenteux , Glucosides/usage thérapeutique , Système rénine-angiotensine/effets des médicaments et des substances chimiques , Inhibiteurs du cotransporteur sodium-glucose de type 2/usage thérapeutique , Équilibre hydroélectrolytique/effets des médicaments et des substances chimiques , Adiposité/effets des médicaments et des substances chimiques , Sujet âgé , Composés benzhydryliques/effets indésirables , Indice de masse corporelle , Eau corporelle/métabolisme , Études cas-témoins , Diabète de type 2/sang , Diabète de type 2/diagnostic , Diabète de type 2/physiopathologie , Impédance électrique , Femelle , Glucosides/effets indésirables , Humains , Études longitudinales , Mâle , Adulte d'âge moyen , Études prospectives , Inhibiteurs du cotransporteur sodium-glucose de type 2/effets indésirables , Facteurs temps , Résultat thérapeutique , Perte de poids/effets des médicaments et des substances chimiques
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