[Gastroenteropancreatic neuroendocrine neoplasms-Heterogeneity, management and perspectives of treatment and research]. / Gastroenteropankreatische neuroendokrine Neoplasien ­ Heterogenität, Management und Perspektiven der Versorgung und Forschung.

The term neuroendocrine neoplasms (NEN) encompasses a molecularly and biologically very heterogeneous group of tumors, which have in common their origin in neuroendocrine cells. The also very heterogeneous subgroup of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is the best classified and investigated group. This article provides a systematic review of the current classification, diagnostics and treatment options of GEP-NEN. In order to achieve a better overview, it was consciously decided not to use an approach based on the primary localization. Instead, a thematic organization according to classification, clinical phenotype, diagnostics and treatment was chosen.

Sparing the hippocampus and the hypothalamic- pituitary region during whole brain radiotherapy: a volumetric modulated arc therapy planning study.

BACKGROUND: Feasibility testing of a simultaneous sparing approach of hippocampus, hypothalamus and pituitary gland in patients undergoing whole-brain radiotherapy (WBRT) with and without a concomitant boost to metastatic sites. INTRODUCTION: Cognitive impairment and hormonal dysfunction are common side effects of cranial radiotherapy. A reduced dose application to the patho-physiologically involved functional brain areas, i.e. hippocampus, hypothalamus and pituitary gland, could reduce these common side effects. While hippocampal sparing is already a common practice to improve cognitive outcome, technical experience of additional combined sparing of the hypothalamus/pituitary gland (HT-P) is insufficient. METHODS: Twenty patients were included in the planning study. In 11 patients, a total dose of 36 Gy of WBRT (2 Gy per fraction) plus a simultaneous integrated boost (SIB) of 9 Gy (0.5 Gy per fraction, total dose: 45 Gy) to the brain metastases was applied. In 9 patients, prophylactic cranial irradiation (PCI) was simulated with a total dose of 30 Gy (2 Gy per fraction). In both patient cohorts, a sparing approach of the hippocampus and the HT-P area was simulated during WBRT. For all treatment plans, volumetric modulated arc therapy (VMAT) was used. Quality assurance included assessment of homogeneity, conformality and target coverage. RESULTS: The mean dose to the hippocampus and HT-P region was limited to less than 50% of the prescribed dose to the planning target volume (PTV) in all treatment plans. Dose homogeneity (HI) of the target volume was satisfying (median HI = 0.16 for WBRT+SIB and 0.1 for PCI) and target coverage (conformation number, CN) was not compromised (median CN = 0.82 for SIB and 0.86 for PCI). CONCLUSION: Simultaneous dose reduction to the hippocampus and the HT-P area did not compromise the PTV coverage in patients undergoing WBRT+SIB or PCI using VMAT. While the feasibility of the presented approach is promising, prospective neurologic, endocrine outcome and safety studies are required.

Circadian regulation of hedonic appetite in mice by clocks in dopaminergic neurons of the VTA.

Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment.

Fractionated radiotherapy and radiosurgery in acromegaly: analysis of 352 patients from the German Acromegaly Registry.

BACKGROUND: If biochemical control of acromegaly is not achieved by operation and medication, radiotherapy may be indicated. OBJECTIVE: To describe fractionated radiotherapy (FRT) and stereotactic radiosurgery (SRS) regarding excess of IGF-1 and pituitary function. DESIGN AND METHODS: A retrospective analysis of 352 patients (4126 patient-years) from the German Acromegaly Registry was performed. Follow-up was 1.0-45.1 years after radiotherapy. Therapeutic success was defined by low or normal IGF-1 according to center-specific reference ranges without (= remission) or on (= controlled disease) suppressive medication. RESULTS: Time between radiotherapy and last follow-up was 13.0 ± 8.2 years for FRT (n = 233) and 8.9 ± 5.0 years for SRS (n = 119, P < 0.001). Median (IQR) basal growth hormone before radiotherapy was 6.3 (2.9-16.2) ng/mL for FRT and 3.5 (1.8-6.9) ng/mL for SRS (P < 0.001). Mean time in uncontrolled state was 3.0 years after FRT and 2.1 years after SRS (95% CI for the difference is 0.1 to 1.6 years, P = 0.021). The 10-year calculated remission rate was 48% for FRT and 52% for SRS (95% CI for the difference is -18 to 26% age points, P = 0.74) and the respective controlled disease rate was 23 and 26%. The odds ratio for adrenocorticotropic or thyreotropic insufficiency was 0.54 (95% CI: 0.30-1.00, P = 0.049) in SRS compared to FRT patients. CONCLUSION: Both after FRT and SRS about 75% of patients with acromegaly are in remission or controlled after 10 years. A slightly faster achievement of target values was observed after SRS. The rate of pituitary insufficiency in FRT patients is significantly higher.

Are hypothalamic- pituitary (HP) axis deficiencies after whole brain radiotherapy (WBRT) of relevance for adult cancer patients? - a systematic review of the literature.

BACKGROUND: Cranial radiotherapy (cRT) can induce hormonal deficiencies as a consequence of significant doses to the hypothalamic-pituitary (HP) axis. In contrast to profound endocrinological follow-up data from survivors of childhood cancer treated with cRT, little knowledge exists for adult cancer patients. METHODS: A systematic search of the literature was conducted using the PubMed database and the Cochrane library offering the basis for our debate of the relevance of HP axis impairment after cRT in adult cancer patients. Against the background of potential relevance for patients receiving whole brain radiotherapy (WBRT), a particular focus was set on the temporal onset of hypopituitarism and the radiation dose to the HP axis. RESULTS: Twenty-eight original papers with a total of 1728 patients met the inclusion criteria. Radiation doses to the HP area ranged from 4 to 97 Gray (Gy). Hypopituitarism incidences ranged from 20 to 93% for adult patients with nasopharyngeal cancer or non-pituitary brain tumors. No study focused particularly on hypopituitarism after WBRT. The onset of hypopituitarism occurred as early as within the first year following cRT (range: 3 months to 25.6 years). However, since most studies started follow-up evaluation only several years after cRT, early onset of hypopituitarism might have gone unnoticed. CONCLUSION: Hypopituitarism occurs frequently after cRT in adult cancer patients. Despite the general conception that it develops only after several years, onset of endocrine sequelae can occur within the first year after cRT without a clear threshold. This finding is worth debating particularly in respect of treatment options for patients with brain metastases and favorable survival prognoses.

[Importance of sleep and circadian rhythm for energy metabolism]. / Bedeutung des zirkadianen Schlafrhythmus für den Energiestoffwechsel.

The circadian clock is a complex and highly specialized network of the human organism and is key for metabolic health. Circadian rhythms are modulated by behavioral patterns, physical activity, food intake as well as sleep loss and sleep disorders. Furthermore, an altered expression of clock genes (e. g. PERIOD1 and 2) can alter circadian rhythms. Chronodisruption, i. e. the alteration of circadian rhythms, is associated with a variety of mental and physical illnesses. Recent studies show a significant association between quantitative and qualitative sleep rhythm disturbances and an increasing prevalence of obesity. Furthermore, reduced sleep quality and duration lead to decreased glucose tolerance and insulin sensitivity, thus increasing the risk of developing type 2 diabetes. In addition to the core components of the metabolic syndrome, there are also changes in hormonal and neuronal signaling pathways impinging on human energy metabolism. This review provides an overview of the current literature highlighting the close link between circadian rhythms and human energy metabolism.

[Physiology and clinical importance of white, beige and brown adipose tissue]. / Physiologie und klinische Bedeutung von weißem, beigem und braunem Fettgewebe.

The metabolic functions of different kinds of adipose tissue are of growing scientific and clinical interest. White adipose tissue is not only an energy store but as a highly active endocrine organ it also plays an essential role in the development of diabetes mellitus, dyslipidemia, arterial hypertension and cardiovascular diseases. Brown adipose tissue, on the other hand, can convert chemical energy into heat and could therefore have an opposing, protective effect. The activation of brown adipose tissue and the induction of the development of adipocytes with the characteristics of brown fat cells could make a significant contribution to the treatment of these civilization diseases. This article provides an overview of the current understanding of the physiology and pathophysiology of different adipose tissue types and the resulting therapeutic potential.

Clinical inertia among patients with type 2 diabetes mellitus treated with DPP-4i and/or SGLT-2i.

OBJECTIVES: Failure to intensify treatment of patients with type 2 diabetes (T2D) in a timely manner is a common challenge. If newer oral anti-diabetic drugs (NOADs) such as dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) do not achieve metabolic control, injectable therapy like insulin or glucagon-like Peptide 1 (GLP-1) receptor agonists are required. We investigated the time in poor glycaemic control (PC, HbA1c > 7%, >7.5%, >8%) in adults with T2D treated with DPP-4i/SGLT-2i until treatment intensification with insulin/GLP-1 or until the most recent documented visit. METHODS: T2D ≥ 18 years were identified from the diabetes patient follow-up registry (DPV), which captures data from diabetes specialist care. Patients with ≥2 documented visits with DPP-4i/SGLT-2i treatment and with the most recent treatment year ≥2015 were included. RESULTS: The study population consisted of 4576 patients treated with DPP-4i/SGLT-2i. A subgroup of 1416 patients were intensified with an injectable therapy. Mean time in PC until intensification with insulin/GLP-1 was 16.7 months (HbA1c > 7%), 15.7 and 15.1 months (HbA1c > 7.5%, HbA1c > 8%) in this subgroup, respectively. Mean time in PC until most recent visit was 12.6, 9.9 and 8.4 months in the subgroup of patients without treatment intensification. CONCLUSIONS: Even with NOADs, a substantial proportion of T2D do not achieve good metabolic control. These findings may be due to individualized target setting for HbA1c, or reluctance of patients and physicians towards injectable therapy. Effective diabetes management strategies are necessary to reduce the risk of adverse outcomes and to increase quality of life in T2D.

[Late effects following childhood cancer treatment : A special challenge for transition medicine]. / Spätfolgen einer Krebsbehandlung im Kindes- und Jugendalter : Eine Herausforderung für die Transitionsmedizin.

BACKGROUND: Childhood cancer survivors are at risk of cancer- and treatment-related chronic health conditions. Since these sequelae may occur years after the end of treatment, many patients are already adults and have completed pediatric oncological care. Thus, successful transition is essential in order to ensure long-term surveillance. OBJECTIVES: The present review outlines the most frequent late effects of childhood cancer treatment. Moreover, difficulties in transition of these patients are discussed and interdisciplinary models of care are presented. RESULTS: Late effects following childhood cancer treatment occur in over two thirds of patients 30 years after the end of the oncological treatment and can affect different organs. The most frequent sequelae are endocrine disturbances, cardiac conditions, and subsequent neoplasms. Many late effects are effectively manageable if detected early. This necessitates an interdisciplinary approach as well as life-long surveillance. CONCLUSIONS: Transition from pediatric to internal medicine care as well as a change in the focus of care, shifting from relapse centered follow-up to late-effects centered surveillance, constitute a special challenge for a successful transition of long-term childhood cancer survivors. Specialized late-effects survivorship clinics offering interdisciplinary care from pediatric oncologists, specialists of internal medicine, and further disciplines enable the early diagnosis and treatment of late-effects.

[Prevention and treatment of cachexia : Exercise and nutritional therapy]. / Prävention und Behandlung der Kachexie : Bewegungs- und Ernährungstherapie.

BACKGROUND: Cachexia is a multifactorial and complex syndrome characterized by progressive functional impairment and ongoing loss in quality of life, which lead to a deterioration of the prognosis for affected patients. The prevalence of cachexia can be very high and is up to 80 % in patients with malignant tumors. OBJECTIVE: The aim of the study was to assess the relevance of exercise and nutrition in the prevention and therapy of cachexia. METHODS: An evaluation of the current literature on exercise and nutritional therapy in patients with cachexia or with advanced stage diseases where a high prevalence of cachexia is probable, was carried out. RESULTS: There is a lack of scientific evidence for the benefits of exercise in cachexia. A major problem of relevant studies was that cachexia was frequently not defined according to valid criteria; however, data indicate a benefit of exercise training in patients with advanced diseases associated with a high prevalence of cachexia. A solely nutritional intervention and dietary counselling seem to be of minimal benefit. The administration of omega 3 fatty acids is controversially discussed. CONCLUSION: Although there is a lack of data on the effects of exercise and nutritional therapy in cachexia, there is evidence for the benefits. The present data indicate the necessity for the use of a multimodal treatment including exercise, nutritional and pharmacological therapy in cachexia. There is a great necessity for prospective studies.

A pitfall in diagnosing Cushing's disease: ectopic ACTH-producing pituitary adenoma in the sphenoid sinus.

PURPOSE: To show a rare case of Cushing's disease and possible cause of failed transsphenoidal surgery. METHOD: We report on a 50-year-old woman suffering from ACTH-dependent Cushing's syndrome. Endocrinological work-up including low-dose/high-dose dexamethasone test (Liddle-test) and CRH test were clearly compatible with pituitary origin. Although an MRI showed no pituitary tumor, CRH-stimulated petrosal sinus sampling revealed a significant central-peripheral gradient in ACTH concentrations, rendering Cushing's disease very likely. The patient underwent transsphenoidal surgery with negative exploration of the pituitary gland. After intraoperative re-evaluation of the preoperative MRI, a "polyp" at the bottom of the sphenoid sinus was identified. The intraoperative microscopic aspect as well as instantaneous sections and cytology of a biopsy confirmed an adenoma, which was then removed. Histological analysis demonstrated an ACTH-producing pituitary adenoma adjacent to respiratory mucous membrane consisting of ciliated epithelium with submucous connective tissue. Postoperatively, ACTH concentrations were decreased and intermittent hydrocortisone substitution treatment was initiated. At the 3-month follow up, Cushing's stigmata were found to be alleviated and the hydrocortisone dosage could be reduced. CONCLUSION: Ectopic pituitary adenoma tissue causing Cushing's disease is extremely rare but a potential cause for surgical failure or re-evaluation.

Disease-related surgery in patients with distant metastatic breast cancer.

INTRODUCTION: This study evaluates the frequency of and indications for disease-related surgical procedures in the palliative breast cancer (BC) situation. PATIENTS & METHODS: Based on a cohort of women who were treated for newly diagnosed BC during a 20-year period (1990-2009), we analyzed 340 patients who developed distant metastatic disease (DMD) until 2011 and died (i.e. still ongoing palliative disease courses were not included). RESULTS: One hundred and twenty-seven surgical procedures were performed in 100 patients (29.4% of all patients with metastatic disease). The most common site for surgery was breast (n = 60, 47.2%). The primary tumor was removed at first diagnosis of DMD in 43 patients (33.9%); sixteen operations (12.6%) were performed for local recurrence. In 37 patients, 50 surgical procedures (39.4%) were necessary to stabilize osseous structures due to metastases. Procedures were rarely performed on other common metastatic sites: lung: n = 1 (0.8%); liver: n = 1 (0.8%), brain: n = 4 (3.1%). When excluding surgery for primary breast tumors at initial diagnosis of DMD from analysis, 34 of 84 surgeries (40.4%) were performed in the first third of survival follow-up (i.e. period of metastatic disease survival); operations in the last two-thirds each totaled 29.8% (n = 25). The median survival after surgery was 16 months (range: 0.5-89 months). CONCLUSIONS: In a cohort of BC patients who had primary or developed secondary DMD, nearly one third of the patients received disease-related surgical procedures during their palliative disease course. This high rate of operations shows that surgery has a clearly established role in the palliative therapy concept.

The post ACOSOG Z0011 era: does our new understanding of breast cancer really change clinical practice?

BACKGROUND: The ACOSOG Z0011 trial (Z0011) expanded our thinking about breast cancer (BC) and showed that limited metastatic disease left behind in the axilla did not compromise oncological safety in a selected group of patients. The aim of the current study was to assess the potential impact of Z0011 on clinical practice by testing the applicability of its criteria to a European patient population. METHODS: We reviewed a consecutive series of 389 sentinel lymph node biopsies (SLNB) performed for invasive BC at the University Hospital Basel between 2003 and 2009 (65.6% of all surgically treated patients, n = 593). RESULTS: When compared to the axillary lymph node dissection (ALND) arm of Z0011, our patients had significantly less advanced LN involvement (≥ 3 LN: 8.5% vs. 21.0%, p = 0.048). Thirty-five patients (9.0%) met the Z0011 inclusion criteria and had 1-2 SLNs with macrometastases (5.9% of all surgically treated BC patients). If the inclusion criteria of Z0011 had been applied, a considerable number of LNs would have been missed in two cases (0.5% of all SLNBs). CONCLUSIONS: The application of the Z0011 led to the omission of completion ALND in less than 10% of all SLNB procedures (<6% of all surgically treated BC patients); therefore, we do not think that the perception of Z0011 as "practice changing" is justified. On the other side, skeptics of the routine implementation of the Z0011 protocol may overestimate its potential hazards. When performing a thorough preoperative clinical axillary staging, the number of patients who would have been undertreated is minimal.

Increasing rates of contralateral prophylactic mastectomy - a trend made in USA?

BACKGROUND: Numerous recent studies conducted in the USA reported a considerable rise in the rates of contralateral prophylactic mastectomy (CPM) in early-stage breast cancer (BC). However, this aggressive surgical approach only showed an evidence-based improvement in prognosis for a small subgroup of high-risk BC patients. We present the first European study reporting CPM rates in an unselected cohort of patients with BC. PATIENTS & METHODS: The data of 881 patients (≤ 80 years) who underwent surgery for stage I-III BC from 1995 to 2009 at the University of Basel Breast Center was analyzed. RESULTS: CPM was performed in 23 of 881 patients (2.6%). Of the entire patient population, 37.5% underwent ipsilateral mastectomy and of those, only 7.0% chose to undergo CPM. Importantly, there was no trend over time in the rate of CPM. Women who chose CPM were significantly younger (54 vs. 60 years, p < 0.001), had more often a positive family history (39.1% vs. 24.4%, p = 0.032) and tumors of lobular histology (30.5% vs. 13.9%, p = 0.035). CONCLUSIONS: Our analysis of CPM rates in BC patients, conducted at a European University breast center, does not show the considerably rising CPM rates observed in the USA. We hypothesize that different medico-social and cultural factors, which are highlighted by a different public perception of BC and a different attitude toward plastic surgery, determine the varying CPM rates between the USA and Europe.

Prognosis of early-stage synchronous bilateral invasive breast cancer.

BACKGROUND: Contradictory data exists concerning the prognosis of patients with synchronous bilateral breast cancer (SBBC). Most authors report a worse prognosis for SBBC patients compared to unilateral breast cancer (UBC) patients. There are a few studies that did not support these findings. This study gives a comprehensive picture of SBBC and tests the hypothesis that outcome of this entity is based on the tumor with the worse prognosis (reference lesion). PATIENTS & METHODS: The data of two prospective Swiss breast cancer databases covering a 20-year period (1990-2009) was reviewed. Forty-six cases of SBBC were identified. In 34 patients with early-stage SBBC, the reference lesions (defined as the tumor with the more advanced stage or, in cases where both tumors had the same stage, the larger tumor) were compared in a case-control approach with 100 patients having UBC (SBBC/UBC ratio = 1/3). The controls were matched for age, time of diagnosis, tumor size, axillary node status, histological grade and estrogen-receptor status. Differences in terms of survival curves were analyzed using the log rank test; the possible correlation between matched groups was evaluated by a frailty Cox model. RESULTS: There were no significant differences in disease-specific survival between SBBC and its unilateral controls (HR, 0.932; 95% CI, 0.322-1.07; p = 0.90). CONCLUSIONS: The prognosis of SBBC was determined by the reference lesion; the contralateral second tumor had no additional impact on outcome.

[Disturbed sleep as risk factor for metabolic syndrome]. / Schlechter Schlaf als Risikofaktor für das metabolische Syndrom.

Sleep disorders, sleep fragmentation, and chronically reduced sleep duration are increasingly common in western societies. In parallel, incidence of the metabolic syndrome and its key components, i.e. type 2 diabetes and obesity, is rapidly increasing. A huge number of epidemiological studies has shown a robust association between disturbed sleep quality, reduced sleep duration and the development of components of the metabolic syndrome. Moreover, there is growing evidence from experimental studies proving a causal link between sleep loss and disturbed human energy homeostasis. Short term sleep loss has been shown to reduce insulin sensitivity and glucose tolerance, increase feelings of hunger by modulating orexigenic/anorexigenic hormonal signaling, and disturb physical activity behavior. This review attempts to present an overview of the presently available literature on the link between sleep loss and disturbed human energy homeostasis, as well as on potential pathophysiological mechanisms.

Sentinel lymph node biopsy in primary breast cancer: trust the radiolabeled colloid method and avoid unnecessary procedures.

BACKGROUND: With regard to the sentinel lymph node (SLN) procedure in breast cancer, the study analyzed the impact of discrepancies between the number of clinically and histologically identified SLN, the impact of removing additional non-hot/non-blue but clinically conspicuous lymph nodes (LN), and whether the application of blue dye for mapping is necessary. METHODS: We analyzed 391 SLN procedures in which 928 SLN were removed. In all cases, radiolabeled colloid and blue dye were used for SLN mapping. RESULTS: In 60 cases (15.3%), additional LN that were not identified by the surgeon were found by histological examination. In 22 cases (5.3%), tissue which clinically resembled an SLN but was histologically connective tissue, was removed. In 76 cases (19.4%), 133 non-hot/non-blue but clinically conspicuous LN were removed. These additionally removed LN, however, did not alter the axillary staging. In 50.8% of the cases (n = 471), the SLN were marked only by radiolabeled colloid. In 27 cases (2.9%), the surgeon identified the LN through blue coloration alone; however, in all of the latter cases, these SLN were not deciding for axillary staging. CONCLUSION: The mapping agents may accumulate in axillary tissue and mimic the existence of an SLN. The radiolabeled colloid method alone gives excellent mapping results. The additional application of blue dye is avoidable. Exact surgical preparation enables removal of the SLN only and avoids removal of LN-containing adjacent tissue. The removal of further clinically identifiable enlarged non-hot LN should only be done if there is strong suspicion of metastatic involvement.

Short-term nocturnal hypoglycaemia increases morning food intake in healthy humans.

AIMS: Hypoglycaemia during wakefulness increases hunger and food intake. Patients with Type 1 diabetes mellitus are at high risk of recurrent hypoglycaemia and weight gain. Given the background of frequent hypoglycaemic episodes during night-time sleep in diabetic patients, we investigated morning food intake after nocturnal hypoglycaemia. METHODS: We tested 16 healthy normal-weight subjects (eight women) on three nights. A linear fall in plasma glucose to a nadir of 2.2 mmol/l within 60 min was induced by insulin infusion immediately after sleep onset ('early hypo') or after about 3.5 h of sleep ('late hypo'). On a control night, no hypoglycaemia was induced. Spontaneous food intake at a breakfast buffet was registered on the subsequent morning. RESULTS: Compared with the control condition (700 +/- 93 kcal), subjects ate more after 'late hypo' (867 +/- 108 kcal; P = 0.041), but not after 'early hypo' (852 +/- 111 kcal; P = 0.130). Analyses of macronutrient fractions revealed that in comparison with the control condition, subjects ate significantly more carbohydrates after both 'late hypo' (277 +/- 25 kcal vs. 206 +/- 23 kcal, P < 0.001) and 'early hypo' (245 +/- 23 kcal, P = 0.048), with this effect being more pronounced after late than early nocturnal hypoglycaemia (P = 0.026). CONCLUSIONS: In healthy subjects, nocturnal hypoglycaemia during sleep stimulates spontaneous food intake the following morning, with carbohydrate intake being especially affected. Effects were more pronounced after 'late hypo', suggesting the influence of temporal dynamics. Although healthy non-diabetic subjects were studied, similar mechanisms may contribute to the frequently observed body weight gain in insulin-treated diabetic patients.

Plasma glucagon decreases during night-time sleep in Type 1 diabetic patients and healthy control subjects.

AIMS: In Type 1 diabetes mellitus (T1DM), the glucagon response to hypoglycaemia is known to disappear within a few months after the onset of the disease, whereas the response to other stimuli remains intact. The dynamics of spontaneous glucagon release have rarely been assessed. We monitored spontaneous glucagon release in T1DM patients and healthy subjects during a 7-h period of night-time sleep. METHODS: Measurements were made in 14 T1DM patients and 14 control subjects matched for age, gender and body mass index after one night's adaptation in our laboratory. Circulating glucose, insulin and glucagon concentrations were measured at 30-min intervals. In diabetic patients, hypoglycaemia (< 3.9 mmol/l) was avoided by infusion of glucose whenever necessary. RESULTS: During the entire night, plasma glucose and serum insulin levels were higher in T1DM patients than in healthy subjects (P < 0.03 and P < 0.001, respectively). Plasma glucagon concentrations decreased throughout the night in both groups (P < 0.001). Glucagon levels were similar in T1DM patients and healthy subjects (P > 0.87). The duration of diabetes (less and more than 5 years) did not affect glucagon secretion (P > 0.87). CONCLUSIONS: Plasma glucagon levels decrease significantly during night-time sleep in healthy control subjects. This nocturnal decrease is preserved in T1DM patients regardless of the duration of diabetes. These observations point to distinct nocturnal regulation of spontaneous glucagon release that does not depend on circulating glucose and insulin levels and is unaltered in T1DM patients.

Mood and cognitive functions during acute euglycaemia and mild hyperglycaemia in type 2 diabetic patients.

INTRODUCTION: Hyperglycaemia at levels above 15 mmol/l has been shown to impair cognitive functions in type 2 diabetic patients, while effects of mild hyperglycaemia and acute euglycaemia on mood and cognition have rarely been compared. We examined mood and cognitive functions in patients with T2DM during acute euglycaemia in comparison with moderate hyperglycaemia. METHODS: One euglycaemic (5 mmol/l) and one hyperglycaemic clamp (10.5 mmol/l) of 90 min each were performed in 15 T2DM patients in a balanced, single-blind, within-subject comparison. Mood, cognitive functions (assessed via short-term memory and attention tests) and symptoms related to glycaemic changes were assessed during a baseline period and during both glycaemic plateaus. In addition, patients estimated their blood glucose level and counterregulatory hormones were measured. RESULTS: None of the assessed aspects of cognitive functions differed between conditions (all p > or = 0.2). Patients rated higher on the well-being scale (p=0.04) and tended to feel less anger (p=0.08) during hyperglycaemia. Self-estimated blood glucose levels were higher during the hyper- than euglycaemic condition (8.6 +/- 2.5 vs 7.2 +/- 1.2 mmol/l; p<0.05) although most individual estimations did not match the actual glucose levels. Counterregulatory hormone levels did not differ (all p>0.25). CONCLUSIONS: Data indicate that T2DM patients are not cognitively impaired by moderate hyperglycaemia (10.5 mmol/l), pointing to the possibility of a glycaemic threshold for cognitive impairments at higher glycaemic levels.