Insulin action in the human brain: evidence from neuroimaging studies.

Thus far, little is known about the action of insulin in the human brain. Nonetheless, recent advances in modern neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), have made it possible to investigate the action of insulin in the brain in humans, providing new insights into the pathogenesis of brain insulin resistance and obesity. Using MEG, the clinical relevance of the action of insulin in the brain was first identified, linking cerebral insulin resistance with peripheral insulin resistance, genetic predisposition and weight loss success in obese adults. Although MEG is a suitable tool for measuring brain activity mainly in cortical areas, fMRI provides high spatial resolution for cortical as well as subcortical regions. Thus, the action of insulin can be detected within all eating behaviour relevant regions, which include regions deeply located within the brain, such as the hypothalamus, midbrain and brainstem, as well as regions within the striatum. In this review, we outline recent advances in the field of neuroimaging aiming to investigate the action of insulin in the human brain using different routes of insulin administration. fMRI studies have shown a significant insulin-induced attenuation predominantly in the occipital and prefrontal cortical regions and the hypothalamus, successfully localising insulin-sensitive brain regions in healthy, mostly normal-weight individuals. However, further studies are needed to localise brain areas affected by insulin resistance in obese individuals, which is an important prerequisite for selectively targeting brain insulin resistance in obesity.

Age-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans.

The dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States. Bromocriptine inhibits prolactin secretion, and patients with hyperprolactinaemia display impaired insulin sensitivity. We therefore hypothesized that low prolactin levels are associated with lower glycaemia and higher insulin sensitivity in healthy subjects. Prolactin levels were determined from fasting serum in participants without diabetes from the cross-sectional Tübingen family study for type 2 diabetes (m/f = 562/1,121, age = 40 ± 13 years, BMI = 30 ± 9 kg/m(2)). A 75 g oral glucose tolerance test was performed, and the area under the glucose curve (AUC(0-120)Glucose) and insulin sensitivity index were calculated. A subgroup (n = 494) underwent hyperinsulinaemic-euglycaemic clamp tests. Prolactin associated positively with insulin sensitivity (p = 0.001, adjusted for gender, age, and BMI). Age strongly interacted (p < 0.0001) with the effect of prolactin on insulin sensitivity, inverting the positive relationship to a negative one in younger participants. Glycated haemoglobin (HbA1c) and AUC(0-120)Glucose correlated negatively with prolactin, and an interaction with age was found as well. Higher prolactin levels are associated with improved insulin sensitivity and lower glucose in individuals without diabetes. This relationship turns to its opposite in younger persons. As prolactin is a proxy for the dopaminergic tone in the central nervous system, these associations may indicate an age-dependent influence of the brain on peripheral insulin sensitivity.

Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl.

BACKGROUND: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. SUBJECT AND METHODS: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. RESULTS: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. CONCLUSION: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.

[Endocrine abnormalities in a young patient with metastatic cancer - case 3/2013]. / Endokrine Veränderungen bei einem jungen Patienten mit metastasiertem Tumorleiden - Fall 3/2013.

HISTORY AND ADMISSION FINDINGS: We report on a 24-year-old male patient who presented with worsening of the general condition and abdominal pain. INVESTIGATIONS: On physical examination, gynecomastia was noted. Laboratory tests showed manifest hyperthyroidism. The beta-hCG levels were markedly increased. By ultrasound, the thyroid gland was hyperperfused without thyroid nodules. Several large echo mixed lesions were found in the liver. The testes appeared normal. DIAGNOSIS: In light of the typical laboratory findings, a non-seminomatous extragonadal germ cell tumor was diagnosed. Hyperthyroidism was most probably HCG induced. TREATMENT AND COURSE: Initially the patient was treated with thyreostatic drugs. After initiation of chemotherapy and a marked decrease in beta-hCG, thyreostatic therapy could be terminated. CONCLUSIONS: Germ cell tumors may cause an increase in beta-hCG concentration. By cross-reacting with the TSH-receptor this could induce hyperthyroidism. Germ cell tumors are therefore a rare differential diagnosis of hyperthyreoidism.

Working memory-related brain activity is associated with outcome of lifestyle intervention.

OBJECTIVE: Lifestyle interventions including reduction of caloric intake are still the most pursued option to treat obesity. However, their outcome in terms of weight loss strongly differs between participants. In our study, we hypothesized that initial differences in brain activation in a food specific memory task are associated with weight change during a lifestyle intervention. DESIGN AND METHODS: Magnetic brain activity was recorded during a one-back visual memory task with food and nonfood pictures in 33 overweight and obese subjects before they underwent a lifestyle intervention. The intervention lasted 6 months and aimed for a reduction in daily caloric intake by 400 kcal. Body mass index (BMI) was determined before and after the intervention. RESULTS: Differences between outer tertiles representing people who increased their BMI by 1.4% ± 1.1% (non-responders) and who reduced their BMI by -6.9% ± 2.6% (responders) are reported. Neuronal activity was related to BMI change in sensor and source space. Non-responders showed higher activation in right inferior frontal and left occipital visual areas, whereas responders showed increased activation in right temporal areas including hippocampus and fusiform gyrus. CONCLUSIONS: Differences in the cerebral response during a food specific memory task indicate an altered cognitive control over food intake. These differences might determine the ability to eat less and successfully lose weight.

Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia.

One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the ß-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the ß-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

Insulin resistant phenotype of polycystic ovary syndrome does not seem to be caused by variation in FTO.

Genetic variation in the FTO gene is associated with increased body weight and reduced insulin sensitivity. We investigated whether genetic variation in FTO is associated with polycystic ovary syndrome (PCOS), a condition also characterized by insulin resistance. Furthermore, we tested whether insulin resistance is specifically associated with genetic variation in FTO in women with PCOS. Sixty-two nondiabetic patients with PCOS defined by the Rotterdam criteria were compared to BMI and age-matched women. Each PCOS case was matched to 2 controls. All participants underwent an oral glucose tolerance test and were genotyped for the single nucleotide polymorphism rs8050136 in the FTO gene. There was no difference in the frequency of FTO genotypes between the PCOS and the non-PCOS groups. In non-PCOS participants, genetic variation in FTO is associated with insulin sensitivity (p=0.03). This association remained significant after adjustment for age and/or BMI (p<= 0.03). In subjects with PCOS, however, FTO did not associate with insulin sensitivity (p=0.67). Genetic variation in FTO does not have an impact on insulin sensitivity in women with PCOS and is therefore not involved in the pathogenesis of the insulin resistant phenotype seen in patients with PCOS.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions.

AIMS/HYPOTHESIS: Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. METHODS: Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (n = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. RESULTS: Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. CONCLUSIONS/INTERPRETATION: Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.

High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention.

AIMS/HYPOTHESIS: Loss of weight and body fat are major targets in lifestyle interventions to prevent diabetes. In the brain, insulin modulates eating behaviour and weight control, resulting in a negative energy balance. This study aimed to test whether cerebral insulin sensitivity facilitates reduction of body weight and body fat by lifestyle intervention in humans. METHODS: The study was performed as an additional arm of the TUebingen Lifestyle Intervention Program (TULIP). In 28 non-diabetic individuals (14 female/14 male; mean ± SE age 42 ± 2 years; mean ± SE BMI 29.9 ± 0.8 kg/m²), we measured cerebrocortical insulin sensitivity by using magnetoencephalography before lifestyle intervention. Total and visceral fat were measured by using MRI at baseline and after 9 months and 2 years of lifestyle intervention. RESULTS: Insulin-stimulated cerebrocortical theta activity at baseline correlated with a reduction in total adipose tissue (r = -0.59, p = 0.014) and visceral adipose tissue (r = -0.76, p = 0.001) after 9 months of lifestyle intervention, accompanied by a statistical trend for reduction in body weight change (r = -0.37, p = 0.069). Similar results were obtained after 2 years. CONCLUSIONS/INTERPRETATION: Our results suggest that high insulin sensitivity of the human brain facilitates loss of body weight and body fat during lifestyle intervention.

Diagnostic value of hemoglobin A1c for type 2 diabetes mellitus in a population at risk.

OBJECTIVE: Because the American Diabetes Association has recently included HbA1c as the primary diagnostic test for the detection of diabetes mellitus (HbA1c ≥6.5%) we investigated its use as screening parameter for diabetes in a cohort at increased risk for the disease. RESEARCH DESIGN AND METHODS: During the last 10 years 2 036 Caucasians at risk to develop type 2 diabetes but not having this diagnosis yet, consecutively underwent a 75 g oral glucose tolerance test (OGTT). HbA1c was determined with the HPLC method (Tosoh A1c 2.2), external and internal quality controls were well within the allowed ranges. RESULTS: The oral glucose tolerance test classified 1 523 individuals as normal glucose tolerant (NGT), 387 as impaired glucose tolerant (IGT) or having impaired fasting glycemia (IFG) and 126 as diabetic. The 6.5% cut-off value of HbA1c classified 47% of the diabetic individuals correctly. Of the remaining 53% diabetic individuals (HbA1c <6.5%) 35% had increased fasting glucose levels, while 65% were only diagnosed by their increased 2 h glucose values. CONCLUSION: A cut-off value of 6.5% HbA1c classifies diabetic subjects with a specificity of 98.7%. However, the sensitivity of 46.8% is low, indicating that more than half of diabetic subjects are missed when using this test. The present data shows that the use of HbA1c as a the primary diagnostic test will reduce diabetes prevalence. Furthermore, it suggests, that HbA1c and OGTT measurements cannot simply be exchanged, but most probably detect and define different categories of diabetes, i. e., categories with different risk of cardiovascular disease.

Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects.

OBJECTIVE: Smell plays an important role in feeding behavior. We therefore tested whether insulin as a postprandial signal is involved in the regulation of olfactory function. RESEARCH DESIGN AND METHODS: We assessed olfactory thresholds in eight lean subjects (age: 34 ± 7 years, M/F: 5/3) before and during a 2-h hyperinsulinemic (1 mU kg(-1) min(-1)) euglycemic clamp and in eight lean fasted subjects (age: 36 ± 6 years, M/F: 5/3) without insulin infusion at the same time of the day. To define odor thresholds, standardized 'sniffing sticks' were used. RESULTS: Odor thresholds decreased from 7.8 ± 1.2 to 6.2 ± 1.1 during euglycemic hyperinsulinemia (P=0.0173), representing an increase in odor threshold. In the control group, odor thresholds were 8.3 ± 1.6 and did not change after 120 min of fasting (8.9 ± 2.2, P=0.6). CONCLUSIONS: Increased insulin levels lead to a reduced smelling capacity, potentially reducing the pleasantness of eating. Therefore, insulin action in the olfactory bulb may be involved in the process of satiation and may thus be of interest in the pathogenesis of obesity.

[Rare differential diagnosis of left brachial pain - Case 6/2010]. / Seltene Differentialdiagnose linksbrachialer Schmerzen - Fall 6/2010.

HISTORY AND ADMISSION FINDINGS: An 83-year old woman was admitted with pain in the left arm and on the left hemithorax. Subsequently, herpes zoster developed on the left arm. The next day, the patient got confused and was agitated. Furthermore, paresis of both legs and the left arm occurred. INVESTIGATIONS: Cranial computed tomography was negative for intracerebral haemorrhage or ischaemia. Examination of cerebrospinal fluid revealed lymphocytic pleocytosis and increased albumin and lactate concentrations. Polymerase chain reaction (PCR) confirmed presence of varicella zoster virus DNA in the cerebrospinal fluid. DIAGNOSIS, TREATMENT AND COURSE: After diagnosis of varicella zoster encephalitis, complicating herpes zoster on the left arm, intravenous treatment with aciclovir was initiated. Consequently, the patient's clinical status improved and the neurological signs declined. CONCLUSIONS: Herpes zoster is a rare differential diagnosis of pain on the left hemithorax and may manifest without skin rashes in the initial stadium. In older patients suffering from herpes zoster, disorientation is common. However, in the presence of focal neurological deficits, varicella zoster encephalitis should definitively be ruled out by spinal tap, even if cranial imaging studies are negative.

The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention.

AIMS/HYPOTHESIS: The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity. METHODS: We genotyped 1,563 participants with an increased risk of type 2 diabetes for K121Q and performed correlational analyses with anthropometric data and variables of insulin sensitivity. For metabolic characterisation, all participants underwent an OGTT. A subgroup of 506 participants additionally underwent a euglycaemic-hyperinsulinaemic clamp. In 342 participants, metabolic traits and anthropometric data were re-evaluated after a 9 month lifestyle intervention. RESULTS: In the overall cohort, K121Q was not associated with measures of obesity, indices of glucose tolerance during OGTT and insulin sensitivity estimated from the OGTT or derived from a euglycaemic-hyperinsulinaemic clamp after appropriate adjustment. However, K121Q did significantly influence the change in insulin sensitivity during lifestyle intervention after appropriate adjustment (p (additive) = 0.0067, p (dominant) = 0.0027). Carriers of the minor allele had an impaired increase in OGTT-derived insulin sensitivity. A similar trend was obtained for clamp-derived insulin sensitivity, but did not reach significance. CONCLUSIONS/INTERPRETATION: In our population of European ancestry, the ENPP1 SNP K121Q influenced the change in insulin sensitivity during lifestyle intervention. Thus, this SNP may determine susceptibility to environmental changes and could predict the success of lifestyle intervention.

[A rare cause of hypoglycaemia in a patient with type 2 diabetes]. / Seltene Ursache für eine Hypoglykämie bei einem Patienten mit Typ-2-Diabetes mellitus.

BACKGROUND: Insulinomas are rare neuroendocrine tumours with an incidence of four cases per million a year. Only few cases of insulinoma in patients with preexisting diabetes mellitus have been reported. CASE: We present a 50-year-old male with type 2 diabetes mellitus who suffered from recurring hypoglycemia. He had gained 20 kilograms of weight in five years. 72-hour fast revealed hypoglycaemia in the presence of inadequately high C-peptide and insulin levels. Magnetic resonance imaging and selective arterial calcium stimulation test confirmed a mass in the body of the pancreas. The tumor was removed surgically. Pathological examination demonstrated a benign insulinoma. Postoperatively, blood glucose levels were within the therapeutic range. The HbA (1c) value was 6.8 % three months after the intervention. CONCLUSION: Clinicians should be alert to insulinoma as a, though rare, differential diagnosis of hypoglycaemia in diabetes, in particular in patients with recurrent, otherwise unexplained hypoglycaemia.

[Malignant pheochromocytomas: about three cases]. / Les phéochromocytomes malins: à propos de trois observations.

The authors report three cases of malignant pheochromocytomas. Metastases occurred in the liver in two cases whereas malignancy was suspected in the third case because of recurrence and local invasion. One case was pregnant at diagnosis of pheochromocytoma. Pheochromocytoma was associated to papillary thyroïd carcinoma in another case. The treatment considered was surgery in all cases.

Triple-point wetting on rough substrates.

The influence of substrate roughness on the wetting scenario of adsorbed van der Waals films is investigated by theory and experiment. Calculating the bending free energy penalty of a solid sheet picking up the substrate roughness, we show that a finite roughness always leads to triple-point wetting reducing the widths of the adsorbed solid films considerably as compared to that of smooth substrates. Testing the theory against our experimental data for molecular hydrogen adsorbed on gold, we find quantitative agreement.

Surface freezing on patterned substrates

We show that the structure of a substrate pattern drastically influences the nature of surface freezing. By using phenomenological theory and computer simulations of a hard sphere fluid next to a substrate formed by a periodic array of fixed spheres, we find that a pattern which is commensurate with the bulk crystal induces complete surface freezing through a cascade of layering transitions. A rhombic pattern, on the other hand, either generates a crystalline sheet which is unstable as a bulk phase or prohibits surface freezing completely.

Interfacial free energy of hard-sphere fluids and solids near a hard wall.

A hard-sphere system near a planar structureless hard wall is considered in thermodynamic equilibrium. The associated interfacial free energies are calculated both for a bulk fluid and a bulk face-centered-cubic crystal along (111), (110), and (100) orientation. Combining Monte Carlo simulations and thermodynamic integration, we obtain the wall-fluid and the wall-solid interfacial free energy over the whole range of possible bulk densities. The "exact" computer simulation data are compared to theoretical approximations. For moderate bulk densities, the wall-fluid interfacial free energies compare reasonably well with scaled-particle theory and density functional results. For the wall-crystal interface, we propose a simple analytical cell theory which yields good agreement with our simulation data over the whole range of bulk crystal densities.