Lot variation and inter-device differences contribute to poor analytical performance of the DCA Vantage™ HbA1c POCT instrument in a true clinical setting.

OBJECTIVES: The glycated haemoglobin fraction A1c (HbA1c) is widely used in the management of diabetes mellitus, and the Siemens DCA Vantage™ point-of-care testing (POCT) instrument offers rapid HbA1c results even far from a clinical laboratory. However, the analytical performance has been questioned, and not much is known about effects of changing reagent lot, instrument and operator. We therefore compared the analytical performance of the DCA Vantage™ with established routine methods (Tosoh G8/G11 ion exchange HPLC) in a true clinical setting at two Danish hospitals. METHODS: We extracted all routine clinical HbA1c results incidentally drawn from the same patient within 48 h (n=960 pairs) and evaluated the effect of reagent lot, operator and instrument. We also performed a prospective method comparison in our diabetes out-patient clinic (n=97). RESULTS: The critical difference (CD) between two POCT results varied between 5.14 and 6.61 mmol/mol (0.47-0.55%), and the analytical imprecision of the DCA Vantage™ (CVA) was >3%. Significant effect of reagent lot and inter-instrument differences were found, whereas no effect of operator was seen. CONCLUSIONS: The DCA Vantage™ HbA1c analysis does not fulfil the prevailing analytical performance specifications, but rigorous validation of new reagent lots and continuous recalibration of instruments may potentially improve the precision substantially. Our findings, therefore, clearly emphasise the necessity of a close collaboration between clinicians and laboratory professionals in the POCT field. Finally, POCT HbA1c results should always be interpreted together with other measures of glycaemic control to avoid inappropriate change of patient treatments due to measurement uncertainty.

Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats.

Major depressive disorder (MDD) is highly associated with dysmetabolic conditions, such as obesity and diabetes mellitus type 2, and the gut microbiota may interact with both disease entities. We have previously shown that a high-fat diet (HFD) exacerbated depressive-like behaviour uniquely in Flinders Sensitive Line (FSL) rats that inherently present with an increased level of depressive-like behaviour compared with Flinders Resistant Line (FRL) rats. We therefore investigated whether multispecies probiotics possessed anti-depressant-like effect in FSL rats or protected against the pro-depressant-like effect of HFD. We also examined blood and cerebral T cell subsets as well as plasma cytokines. Lastly, we investigated the effect of HFD in outbred Sprague-Dawley (SD) rats to substantiate the association between depressive-like behaviour and any immunological measures affected by HFD. HFD exacerbated the depressive-like behaviour in FSL rats in the forced swim test, whereas SD rats remained unaffected. Probiotic treatment completely precluded the pro-depressant-like effect of HFD, but it did not affect FSL rats on control diet. Cerebral T lymphocyte CD4/8 ratios closely mirrored the behavioural changes, whereas the proportions of Treg and Th17 subsets were unaltered. No association between blood and brain CD4/8 ratios were evident; nor did plasma cytokine levels change as a consequence of HFD of probiotic treatment. Our findings suggest that MDD may hold a dysmetabolic component that responds to probiotic treatment. This finding has wide implications owing to the high metabolic comorbidity in MDD. Furthermore, the close association between depressive-like behaviour and cerebral T cell populations demonstrate lymphocyte-brain interactions as a promising future research area in the field of psychoneuroimmunology.

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction.

Brown adipose tissue thermogenesis at the cost of energy is not only important for the development of obesity, but also possesses great promise in anti-obesity treatment. Uncoupling protein 1 (UCP1) expression has been reported to be under control of the intracellular deacetylase SIRT1. Here, we investigated the effect and mechanism of inflammation and sirtuin-1 (SIRT1) activation on the induction of thermogenic genes in immortalized brown adipocytes incubated with LPS or IL1ß and mice with elevated inflammatory tone. In vitro stimulation of brown adipocytes with dibutyryl cyclic adenosine monophosthate (dbcAMP) reduced the expression of deleted in breast cancer-1 (Dbc1) (SIRT1 inhibitor) and increased the Ucp1 expression. Silencing of SIRT1 attenuated dbcAMP induction of Ucp1. In contrast, IL1ß increased the expression of Dbc1 and greatly reduced the induction of Ucp1. Similarly, in vivo studies revealed decreased expression of Ucp1 in brown adipose tissue (BAT) in mice chronically infused with LPS. Resveratrol, a known SIRT1 activator, partly rescued the Ucp1 downregulation by inflammation in both the cell cultures and mice. Here, we describe how the expression of Ucp1 in BAT is controlled via SIRT1 and is reduced under inflammation and can be rescued by SIRT1 activation by resveratrol. We suggest the reduced UCP1 expression under inflammation is mediated by the increased expression of DBC1, which inhibits SIRT1 activity.

A robust method to screen detergents for membrane protein stabilization, revisited.

This report is a follow up of our previous paper (Lund, Orlowski, de Foresta, Champeil, le Maire and Møller (1989), J Biol Chem 264:4907-4915) showing that solubilization in detergent of a membrane protein may interfere with its long-term stability, and proposing a protocol to reveal the kinetics of such irreversible inactivation. We here clarify the fact that when various detergents are tested for their effects, special attention has of course to be paid to their critical micelle concentration. We also investigate the effects of a few more detergents, some of which have been recently advertised in the literature, and emphasize the role of lipids together with detergents. Among these detergents, lauryl maltose neopentyl glycol (LMNG) exerts a remarkable ability, even higher than that of ß-dodecylmaltoside (DDM), to protect our test enzyme, the paradigmatic P-type ATPase SERCA1a from sarcoplasmic reticulum. Performing such experiments for one's favourite protein probably remains useful in pre-screening assays testing various detergents.

GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists are a new group of antidiabetic medications quickly gaining popularity. We aimed to examine behavioural and neuroendocrine changes following chronic treatment with GLP-1 receptor agonists in animal models. METHODS: The effects of chronic treatment with GLP-1 receptor agonists were determined on behavioural parameters [anxiety level in the light-dark compartment test, the motor activity in automated activity cages, immobility in the forced swimming test (FST)] and on corticosterone release in mice. The possible antidepressant effect of chronic liraglutide treatment was also studied in Flinders Sensitive Line (FSL) rats, a genetic model of depression. RESULTS: Two weeks of treatment with exenatide (10 µg/kg twice daily) or liraglutide (1200 µg/kg once daily) did not affect the anxiety level in a light-dark compartment test nor induce an antidepressant-like effect in the FST in mice. Moreover, chronic treatment with liraglutide had no effect on depression-related behaviour in FSL rats. Interestingly, hypolocomotion induced by the drugs in mice disappeared after chronic dosing. Both of the GLP-1 receptor agonists induced robust increases in corticosterone levels in mice under basal conditions as well as in the case of combination with swimming stress. Remarkably, exenatide was as potent a stimulator of corticosterone release after 2 weeks as after acute administration. CONCLUSIONS: The increases in corticosterone release seen after acute exenatide or liraglutide treatment do not abate after 2 weeks of treatment demonstrating that tolerance does not develop towards this particular effect of GLP-1 agonists.

Chronic lipopolysaccharide infusion fails to induce depressive-like behaviour in adult male rats.

BACKGROUND: Chronic inflammation is implicated in numerous diseases, including major depression and type 2 diabetes mellitus (T2DM). Since depression and T2DM often co-exist, inflammatory pathways are suggested as a possible link. Hence, the establishment of an immune-mediated animal model would shed light on mechanisms possibly linking depression and metabolic alterations. OBJECTIVE: In this study we investigated a behavioural and metabolic paradigm following chronic infusion with low doses of lipopolysaccharide (LPS) using osmotic minipumps in male rats. METHODS: Behavioural testing consisted of evaluating activity level in the open field and depressive-like behaviour in the forced swim test. Metabolic assessment included measurement of body weight, food and water intake, and glucose and insulin levels during an oral glucose tolerance test. RESULTS: LPS-infused rats showed acute signs of sickness behaviour, but chronic LPS infusion did not induce behavioural or metabolic changes. CONCLUSION: These results suggest that although inflammation is immediately induced as indicated by acute sickness, 4 weeks of chronic LPS administration via osmotic minipumps did not result in behavioural changes. Therefore, this paradigm may not be a suitable model for studying the underlying mechanisms that link depression and T2DM.

Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.

OBJECTIVE: Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM. METHODS: The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers. RESULTS: It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6. CONCLUSION: In conclusion, we hypothesise that imbalances of the microbiota-gut-brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour.

Chronic high-fat diet increases acute neuroendocrine stress response independently of prenatal dexamethasone treatment in male rats.

OBJECTIVE: Intrauterine growth restriction (IUGR) has been associated with metabolic disorders later in life such as obesity and diabetes as well as psychiatric disorders such as depression and schizophrenia. Therefore, we wanted to investigate whether behavioural, metabolic or neuroendocrine abnormalities could be provoked or exacerbated by a high-fat diet (HFD) in an experimental model of IUGR. METHODS: Pregnant dams were exposed to dexamethasone (DEX) in the third gestational week to induce IUGR. Late adolescent male offspring of DEX- and vehicle-treated dams were then fed a HFD or standard chow for 8 weeks and subjected to a variety of assessments. RESULTS: Only diet affected the hypothalamus-pituitary-adrenal (HPA) axis stress response, as HFD doubled the observed corticosterone levels following acute restraint. HFD and prenatal DEX exposure concomitantly exacerbated depressive-like behaviour in the forced swim test, even though no interaction was seen. Prenatal DEX treatment tended to increase the basal acoustic startle response (ASR), while an interaction between HFD and DEX was present in the ASR pre-pulse inhibition suggestive of fundamental changes in neuronal gating mechanisms. Metabolic parameters were only affected by diet, as HFD increased fasting glucose and insulin levels. CONCLUSION: We conclude that chronic HFD may be more important in programming of the HPA axis stress responsiveness than an adverse foetal environment and therefore potentially implies an increased risk for developing psychiatric and metabolic disease.

A group-based intervention for diabetes-related emotional distress among emerging adults with type 1 diabetes: A pilot study.

AIMS: To assess diabetes-related emotional distress (DD) in emerging adults with type 1 diabetes (T1D) and assess a group-based intervention's impact. METHODS: To investigate DD we used data from the Problem Areas in Diabetes Questionnaire comprising 20 items (PAID-20). Furthermore, changes in the WHO Well-Being Index comprising five items (WHO-5) and glycated haemoglobin (HbA1c) were analysed. The intervention was evaluated using follow-up data from the emerging adults who participated. RESULTS: From 2021 to 2023, we screened 180 emerging adults using PAID-20. DD (PAID-20≥30) was prevalent in 25.0 % (95 % CI 18.9; 32.0 %), and associated with the female sex, higher HbA1c and WHO-5 < 50. Continuous subcutaneous insulin infusion at baseline was associated with PAID-20<30. 21 individuals attended a group-based intervention. At one-week follow up PAID-20 was reduced (29.1 ± 15.4 vs. 41.3 ± 12.1 at baseline, p = 0.003), and at nine-twelve months' follow-up HbA1c was reduced (59.3 ± 15.3 mmol/mol vs. 68.0 ± 17.4 mmol/mol at baseline, p = 0.012). CONCLUSIONS: This pilot study demonstrated that 25 % of the investigated emerging adults with T1D experienced DD (PAID-20≥30) associated with four clinical factors. We found a reduction in HbA1c and a short-term reduction in PAID-20 following the group-based intervention.

The anti-inflammatory agent 5-ASA reduces the level of specific tsRNAs in sperm cells of high-fat fed C57BL/6J mouse sires and improves glucose tolerance in female offspring.

INTRODUCTION: The prevalence of obesity and associated comorbidities have increased to epidemic proportions globally. Paternal obesity is an independent risk factor for developing obesity and type 2 diabetes in the following generation, and growing evidence suggests epigenetic inheritance as a mechanism for this predisposition. How and why obesity induces epigenetic changes in sperm cells remain to be clarified in detail. Yet, recent studies show that alterations in sperm content of transfer RNA-derived small RNAs (tsRNAs) can transmit the effects of paternal obesity to offspring. Obesity is closely associated with low-grade chronic inflammation. Thus, we evaluated whether the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) could intervene in the transmission of epigenetic inheritance of paternal obesity by reducing the inflammatory state in obese fathers. METHODS: Male C57BL/6JBomTac mice were either fed a high-fat diet or a high-fat diet with 5-ASA for ten weeks before mating. The offspring metabolic phenotype was evaluated, and spermatozoa from sires were isolated for assessment of specific tsRNAs levels. RESULTS: 5-ASA intervention reduced the levels of Glu-CTC tsRNAs in sperm cells and improved glucose tolerance in female offspring fed a chow diet. Paternal high-fat diet-induced obesity per se had only a moderate impact on the metabolic phenotype of both male and female offspring in our setting. CONCLUSION: The results indicate that the low-grade inflammatory response associated with obesity may be an important factor in epigenetic inheritance of paternal obesity.

Estrogen prevents increased hepatic aquaporin-9 expression and glycerol uptake during starvation.

In starvation, glycerol is released from adipose tissue and serves as an important precursor for hepatic gluconeogenesis. By unknown sex-specific mechanisms, women suppress the endogenous glucose production better than men and respond to metabolic stress with higher plasma glycerol levels. Hepatic glycerol uptake is facilitated by aquaporin-9 (AQP9), a broad-selectivity neutral solute channel, and represents an insulin-regulated step in supplying gluconeogenesis with glycerol. In the present study, hepatic AQP9 abundance was increased 2.6-fold in starved male rats as assessed by immunoblotting and immunohistochemistry. By contrast, starvation had no significant effect on hepatic AQP9 expression in female rats. Coordinately, plasma glycerol levels remained unchanged with starvation in male rats, whereas it was increased in female rats. The different responses to starvation were paralleled by higher glycerol permeability in basolateral hepatocyte membranes from starved male rats compared with starved females. Ovariectomy led to a starvation-response pattern identical to that observed in male rats with increased hepatic AQP9 expression and unchanged plasma glycerol levels. In cultured hepatocytes, 17ß-estradiol and the selective estrogen receptor α-agonist, propyl pyrazole triol, caused a decrease in AQP9 expression. Our results support that a sex-specific regulation of the hepatic glycerol channel AQP9 during starvation contributes to the higher plasma glycerol levels observed in women during fasting and possibly results in a lower cytosolic availability of glycerol. Furthermore, the sexual dimorphism in the hepatic handling of glycerol during starvation might be explained by 17ß-estradiol preventing the starvation-induced increase in hepatic AQP9 abundance.

Microarray expression analysis in delayed cardioprotection: the effect of exercise, AICAR, or metformin and the possible role of AMP-activated protein kinase (AMPK).

AMP-activated protein kinase (AMPK) is an enzyme which may be involved in cardioprotective mechanisms in the ischemic heart. Exercise, AICAR, and metformin, all known activators of AMPK, induce delayed cardioprotection which protects the heart against ischemia-reperfusion injury. The objective was to determine the effect of exercise, AICAR, and metformin on gene expression profile and to demonstrate possible interactions in different genes and functions. Rats were divided into either an exercise, AICAR, metformin, or control group. 3, 12, and 24 h after either a single bout of exercise training, a single injection of AICAR or a single dose of metformin, hearts were removed and gene expression profiles were analyzed in tissue from the left ventricle using Affymetrix gene chip probe arrays. Ingenuity Pathway Analysis (IPA) tool was used to analyze the regulated genes for relevant functions and diseases. Each gene chip identified up to 30,000 different probesets of which Ingenuity identified approximately up to 12,000 genes. A total of 147, 304, and 114 different genes in the left ventricle whose expressions were altered >2.0-fold were identified in the exercise, AICAR, and metformin group, respectively. Seventy eight different genes were overlapping the exercise and AICAR group at 24 h. Ingenuity identified six overlapping genes between the exercise, AICAR, and metformin groups including NR4A3, TNFRSF12A, HBB, PENK, PAP, and MAP4K4. IPA software revealed an overabundance of focus molecules in all three intervention groups involving functions related to cell death, cellular growth and proliferation, gene expression and cancer. Exercise, AICAR, and metformin regulate several genes in the rat myocardium with the majority of overlapping genes observed in the exercise and AICAR group. Changes in gene programming mainly involved inflammatory and opioid systems recognized as cardioprotective pathways. Some of these genes may represent possible candidate genes involved in the molecular mechanisms of AMPK-induced delayed PC.

A diet-induced gut microbiota component and related plasma metabolites are associated with depressive-like behaviour in rats.

It is well-established in preclinical studies that various probiotics may improve behaviours related to psychiatric disease. We have previously shown that probiotics protected against high-fat diet (HFD)-induced depressive-like behaviour in Flinders Sensitive Line (FSL) rats, whereas FSL rats on control (CON) diet were unaffected. Therefore, we hypothesised that a dysmetabolic component of depression may exist that involves the gut microbiota and that such component may be reflected in the plasma metabolome. The aims of the present study post hoc analyses were 1) to study the effect of probiotics on gut microbiota composition and its association with depressive-like behaviour in FSL rats, and 2) to identify plasma metabolites associated with gut microbiota and depressive-like behaviour. Forty-six FSL rats were fed CON or HFD and treated with multi-species probiotics (nine Bifidobacterium, Lactococcus and Lactobacillus species) for 12 weeks. Faecal samples were collected for 16S rRNA (VR4) gene amplicon sequencing (Illumina MiSeq), and an untargeted plasma metabolomics was performed. We found that probiotics increased the relative faecal abundance of the Bifidobacterium, Lactococcus and Lactobacillus genera in HFD-fed rats only. Also, a HFD-induced microbiota component associated with depressive-like behaviour was identified, and probiotics improved the component score. Finally, the plasma levels of 44 metabolites correlated with the depression-related microbiota component, and three such metabolites had good predictive ability for depressive-like behaviour. Potentially, our findings imply that a subtype of depression characterised by a diet-induced, pro-depressant gut microbiota may exist and that analysis of related plasma metabolites may reveal aberrant microbiota functioning related to depression.

Gastric Emptying Time and Volume of the Small Intestine as Objective Markers in Patients With Symptoms of Diabetic Enteropathy.

BACKGROUND/AIMS: Patients with diabetes mellitus (DM) often suffer from gastrointestinal (GI) symptoms, but these correlate poorly to established objective GI motility measures. Our aim is to perform a detailed evaluation of potential measures of gastric and small intestinal motility in patients with DM type 1 and severe GI symptoms. METHODS: Twenty patients with DM and 20 healthy controls (HCs) were included. GI motility was examined with a 3-dimensional-Transit capsule, while organ volumes were determined by CT scans. RESULTS: Patients with DM and HCs did not differ with regard to median gastric contraction frequency (DM: 3.0 contractions/minute [interquartile range {IQR}, 2.9-3.0]; HCs: 2.9 [IQR, 2.8-3.1]; P = 0.725), amplitude of gastric contractions (DM: 9 mm [IQR, 8-11]; HCs: 11 mm (IQR, 9-12); P = 0.151) or fasting volume of the stomach wall (DM: 149 cm3 [IQR, 112-187]; HCs: 132 cm3 [IQR, 107-154]; P = 0.121). Median gastric emptying time was prolonged in patients (DM: 3.3 hours [IQR, 2.6-4.6]; HCs: 2.4 hours [IQR, 1.8-2.7]; P = 0.002). No difference was found in small intestinal transit time (DM: 5 hours [IQR, 3.7-5.6]; HCs: 4.8 hours [IQR, 3.9-6.0]; P = 0.883). However, patients with DM had significantly larger volume of the small intestinal wall (DM: 623 cm3 [IQR, 487-766]; HCs: 478 cm3 [IQR, 393-589]; P = 0.003). Among patients, 13 (68%) had small intestinal wall volume and 9 (50%) had gastric emptying time above the upper 95% percentile of HCs. CONCLUSION: In our study, gastric emptying time and volume of the small intestinal wall appeared to be the best objective measures in patients with DM type 1 and symptoms and gastroenteropathy.

Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats.

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4-5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser(473) phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P < 0.05 vs. Cx), whole body insulin resistance (P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser(473) phosphorylation. The ESC treatment normalized corticosterone secretion (P < 0.05 vs. LBW), whole body insulin sensitivity (P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P < 0.05), and red muscle PKB Ser(473) phosphorylation (P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

Effects of GH in human muscle and fat.

Skeletal muscle is the major constituent of lean body mass and a major determinant of energy expenditure both at rest and during physical activity. Growth hormone, in turn, influences muscle mass as well as energy expenditure. Growth hormone substitution in adults increases muscle mass by 5-10%, but part of the effect is attributed to rehydration rather than protein accretion. In addition, GH regulates substrate metabolism in muscle and in particular antagonizes insulin-stimulated glucose disposal. This effect is linked to increased free fatty acid (FFA) flux but the molecular mechanisms remain unclear. During fasting, GH-induced insulin resistance may be favorable by reducing the demand of gluconeogenesis from protein. But in the postprandial phase, GH exposure may compromise glucose tolerance via the same mechanisms. Understanding the mechanisms whereby GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes.

[Symptoms of diabetic gastroenteropathy in patients with diabetes].

Abdominal pain, nausea, vomiting, diarrhoea, constipation, and faecal incontinence are common symptoms of diabetic gastroenteropathy and often have a major impact on quality of life. The symptoms are usually caused by widespread dysfunction of the gastrointestinal tract. Hence, diagnosis requires panenteric assessment. The general principles of management are glycaemic control, diet, prokinetics, laxatives, and in selected cases, gastric electrical stimulation, which is summarised in this review.

Enteric cholinergic neuropathy in patients with diabetes: Non-invasive assessment with positron emission tomography.

BACKGROUND: 11 C-Donepezil positron emission tomography (PET) allows non-invasive assessment of cholinergic innervation of visceral organs. We aimed to compare cholinergic innervation in the gut in patients with diabetes mellitus (DM) and in healthy controls (HC). METHODS: 11 C-Donepezil PET and computed tomography (CT) were performed in 19 patients with type 1 DM and gastrointestinal symptoms and in 19 age- and sex-matched HC in a cross-sectional design. KEY RESULTS: All patients had severe gastrointestinal symptoms when assessed by standard questionnaires. DM patients had significantly increased volume of the small intestinal wall (DM: median 557 cm3 [interquartile range [IQR] 446-697] vs HC median: 448 cm3 [IQR; 341-518; P < .01]), and the 11 C Donepezil PET uptake was reduced in patients (DM: median 7.08 standardized uptake value [SUV] [IQR; 5.94-8.43] vs HC: median 9.18 SUV [IQR; 8.57-10.11; P < .01]). A similar pattern was found in colon (DM: median volume 1064 cm3 [IQR; 882-1312] vs HC: median 939 cm3 [IQR; 785-1081; P = .13] and DM: median 1.22 SUV (IQR; 1.08-1.36) vs HC: median 1.42 SUV (IQR; 1.32-1.53; P = .03). Furthermore, patients had significantly reduced pancreatic volume (DM: median 53 cm3 [IQR; 41-69] vs HC: median 98 cm3 [IQR;82-110; P < .01]) and reduced PET uptake of the pancreas (DM: median 13.14 SUV [IQR;9.58-15.82] vs HC: median 21.46 SUV [IQR;18.97-24.06; P < .01]) as well as the adrenal gland (DM: median 7.62 SUV [IQR;7.61;15.82] vs HC: median 15.51 SUV [IQR;12.22;19.49; P = .03]). CONCLUSION AND INFERENCES: Assessed with 11 C-Donepezil PET/CT, patients with DM and severe bowel symptoms have reduced cholinergic innervation of the gut indicative of parasympathetic denervation.

Colonic motility in patients with type 1 diabetes and gastrointestinal symptoms.

BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with diabetes mellitus (DM). The electromagnetic 3D-Transit system allows assessment of regional transit times and motility patterns throughout the GI tract. We aimed to compare GI transit times and detailed motility patterns of the colon in patients with DM and GI symptoms to those of healthy controls (HC). We further aimed to determine whether any abnormalities in motility were reversible by cholinergic stimulation. METHODS: We compared 18 patients with DM with 20 HC by means of the 3D-Transit system. Patients were studied before and during oral administration of 60 mg pyridostigmine. KEY RESULTS: Compared to HC, patients had prolonged gastric emptying (DM: 3.3 hours (interquartile range (IQR) 2.6-4.6); HC: 2.3 hours (IQR 1.7-2.7) (P < .01)), colonic transit time (DM: 52.6 hours (IQR 23.3-83.0); HC: 22.4 hours (IQR 18.9-43.6) (P = .02)), and whole gut transit time (DM: 69.4 hours (IQR 32.9-103.6); HC: 30.3 hours (IQR 25.2-49.9) (P < .01)). In addition, compared to HC, patients had prolonged transit time in the ascending colon (DM: 20.5 hours (IQR 11.0-44.0); HC: 8.0 hours (IQR 3.8-21.0) (P < .05)) and more slow retrograde movements in the colon (DM: 2 movements (IQR 1-4); HC: 1 movement (IQR 0-1) (P = .01)). In patients, pyridostigmine increased the number of bowel movements (P < .01) and reduced small intestine transit times (P < .05). CONCLUSIONS: Patients with DM and GI symptoms have longer than normal GI transit times. This is only partly reversible by pyridostigmine. The increased number of retrograde colonic movements in patients could potentially explain the abnormally long transit time in proximal colon.