Burden of selected chronic non-communicable diseases in a primary healthcare setting in Nuuk, Greenland, compared to a Danish suburb.

INTRODUCTION: Noncommunicable diseases (NCDs) constitute a massive global burden and are the leading cause of death and disability worldwide. In Greenland, the prevalence of NCDs has historically been low. However, during the past approximately 70 years, life circumstances have changed dramatically resulting in increased life expectancy. Today, the proportion of inhabitants in Greenland ≥65 years has nearly tripled since the 1980s, and the prevalence of obesity and diabetes has increased rapidly within the past decades. The aim of this study was to describe the burden of selected NCDs in a primary care setting in Nuuk and compare it to a modern westernized suburban general practice in Denmark. METHODS: The study was performed as a cross sectional register-based study using data extracted from the electronic medical records (EMR) based on diagnosis codes from inhabitants living in Nuuk, Greenland, and a suburb in Denmark. Estimates of prevalence were age-standardized to the WHO world standard population. RESULTS: In both Nuuk and the Danish suburb, the highest prevalence was observed for hypertension (13.2% for both populations), followed by asthma (4.4 and 9.5%, respectively) and diabetes (4.3 and 2.9%, respectively). The age-standardized prevalences of diabetes, COPD, atrial fibrillation, and heart failure, were significantly higher in Nuuk, while seven NCDs including asthma, ischemic heart disease, arthritis urica, psoriasis, hyperthyreosis, hypothyreosis and osteoporosis were significantly higher in the Danish suburb. CONCLUSION: In contrast to the disease pattern observed in Greenland in the last century, the prevalence of diagnosed NCDs in Nuuk is no longer rare. Thus, the overall prevalence of NCDs in the population of Nuuk is now comparable to or even higher than in the suburb in Denmark. This calls for increased focus on all NCDs in the primary healthcare system in Greenland and adaption of the primary healthcare services to a changed disease spectrum.

Christmas article: Snacking preferences at the office during the Christmas season ­ a secret intervention study among diabetes researchers.

Introduction To quantify the effect of Christmas vs. New Year's resolutions season on snacking preferences by measuring intake of four different snacks. Methods Prospective ad libitum intervention snacking study with four combinations of sweet/savory and fatty/non-fatty snacks: cookies, candy, TUC crackers, and rye crackers. A snacking buffet, continuously refilled by a secret Santa, was provided during the Christmas season and New Year's Resolutions season by the secret Santas of the office. Participants were diabetes researchers and were not informed about the study before the end of data collection. The main outcome was daily intake (g) of the four snacks. Results In general, the intake of candy was high compared to the other snacks. The average intake of cookies was significantly higher during the Christmas season compared to New Year's resolution season (8 g/day/participant, p = 0.03), but decreased when approaching Christmas and increased again as time passed by after Christmas (although not significantly). The strongest correlation between the intake of snacks was found between the two sweet snacks, i.e., candy and cookies. Conclusion Researchers have a high preference for sweet foods, especially candy. Irrespective of the type of snack, the preference for cookies was high during the Christmas season but seemed to decrease with decreasing proximity to Christmas, hence, canceling Christmas will unlikely improve diet quality. In fact, we encourage further research to consider whether having Christmas all year could be a potential prevention strategy in the combat of the obesity pandemic. Funding none. Trial registration none.

High quality of diabetes care in Greenland since the launch of Steno Diabetes Center Greenland 2020 - geographical disparities need attention.

The aim of this study was to estimate the prevalence of diagnosed diabetes in Greenland and evaluate quality of care according to sex, region and healthcare unit within regions. Data on all inhabitants registered with diabetes were extracted from the electronic medical record. We found a crude prevalence of diagnosed diabetes in the population aged ≥ 20 years to be 4.7%, and the prevalence of diabetes standardised to the WHO world population was 4.0%. Compared to males, a significantly higher proportion of females had mean glycated haemoglobin (HbA1c) level below 7% (68.9% vs. 57.5%) and blood pressure below 140/90 mmHg (83.4% vs. 73.5%). Regarding healthcare unit within regions, quality of care was higher in regional cities compared to smaller cities, concerning proportion of persons having blood pressure measured regularly (86.0% vs. 71.7%), urine tested for albuminuria (70.6% vs. 51.2%), receiving eye examination (86.9% vs. 79.5%) and foot examination (87.9% vs. 79.4%). In conclusion, the prevalence of diagnosed diabetes in Greenland is the highest reported yet. The overall quality of diabetes care was high and significantly improved compared to 2018. We observed geographical inequality in diabetes care and improvements in the quality of care in specific remote locations are necessary to minimise health care disparities.

Reporting chronic kidney disease in Greenland.

Background: Chronic kidney disease (CKD) is a major health burden affecting more than 10% of the global population. It is a multifactorial disease with many risk factors attributed lifestyle diseases. The prevalence of CKD in Greenland is unknown; however, the prevalence of risk factors contributing to CKD is increasing.Objectives: To estimate the prevalence of CKD in Greenland.Methods: The study was a cross-sectional register-study including all Greenlandic residents aged ≥20 years with serum creatinine analysis within the last 2 years. We identified those with CKD based on eGFR and UACR and those registered with a CKD diagnosis code. Two limitations of the study are possible lack of data completeness and the reliance of a single time point to report CKD.Results: A total of 2,157 patients were identified with CKD with an age-standardised prevalence of 3.01%. Only 75 patients were registered with a diagnosis code for CKD. Approximately 80% of patients were classified with CKD stages 1-2.Conclusion: This is the first study reporting CKD in Greenland. We found a lower prevalence of CKD than reported by other studies, and a low number of patients correctly diagnosed with CKD. We call for increased awareness and diagnosis coding of CKD in Greenland.

PICK1-Deficient Mice Maintain Their Glucose Tolerance During Diet-Induced Obesity.

Context: Metabolic disorders such as obesity represent a major health challenge. Obesity alone has reached epidemic proportions, with at least 2.8 million people worldwide dying annually from diseases caused by overweight or obesity. The brain-metabolic axis is central to maintain homeostasis under metabolic stress via an intricate signaling network of hormones. Protein interacting with C kinase 1 (PICK1) is important for the biogenesis of various secretory vesicles, and we have previously shown that PICK1-deficient mice have impaired secretion of insulin and growth hormone. Objective: The aim was to investigate how global PICK1-deficient mice respond to high-fat diet (HFD) and assess its role in insulin secretion in diet-induced obesity. Methods: We characterized the metabolic phenotype through assessment of body weight, composition, glucose tolerance, islet morphology insulin secretion in vivo, and glucose-stimulated insulin secretion ex vivo. Results: PICK1-deficient mice displayed similar weight gain and body composition as wild-type (WT) mice following HFD. While HFD impaired glucose tolerance of WT mice, PICK1-deficient mice were resistant to further deterioration of their glucose tolerance compared with already glucose-impaired chow-fed PICK1-deficient mice. Surprisingly, mice with ß-cell-specific knockdown of PICK1 showed impaired glucose tolerance both on chow and HFD similar to WT mice. Conclusion: Our findings support the importance of PICK1 in overall hormone regulation. However, importantly, this effect is independent of the PICK1 expression in the ß-cell, whereby global PICK1-deficient mice resist further deterioration of their glucose tolerance following diet-induced obesity.

Low Prevalence of Chronic Obstructive Pulmonary Disease in Greenland-A Call for Increased Focus on the Importance of Diagnosis Coding.

The aim of this study was to estimate the prevalence of patients diagnosed with chronic obstructive pulmonary disease (COPD) according to age, gender, and residence in Greenland and to investigate the associated quality of care. The study was performed as an observational cross-sectional study using data on patients diagnosed with COPD, extracted from the electronical medical record (EMR) in Greenland. The total prevalence of patients aged 20-79 years diagnosed with COPD in Greenland in 2022 was 2.2%. The prevalence was significantly higher in the capital Nuuk compared to the remaining parts of Greenland (2.4% vs. 2.0%, respectively). Significantly more women than men were diagnosed with COPD, but the lung function of men was found to be significantly reduced/impaired compared to women. The prevalence of patients aged 40 years or above was 3.8%. The quality of care was significantly higher among patients living in Nuuk compared to the remaining parts of Greenland for eight out of ten quality indicators. The prevalence of COPD in Greenland is lower than in other comparable populations and might be underestimated. Continued focus on early detection of new cases and initiatives to improve and expand monitoring of quality-of-care measurements, including both additional clinical and patient reported outcomes, are recommended.

Low prevalence of diagnosed asthma in Greenland - a call for increased focus on diagnosing.

The aim of this study was to estimate prevalence of patients with asthma in Greenland according to age, gender and residence and to investigate the associated quality of care. The study was performed as a cross-sectional study with data extracted from the Greenlandic electronical medical record. A total of 870 patients aged 12 years or above were diagnosed with asthma at the end of 2022, corresponding to a prevalence of 1.9%. In 2020, the total prevalence was 0.2%. The prevalence of patients aged 12 years or above with asthma was highest among patients in Nuuk (3.3%) compared with patients in the remaining parts of Greenland (1.1%). More women than men were diagnosed with asthma, and the prevalence increased with age from 20 to 59 years. The prevalence of current smokers was high among the asthma population. The quality of care was significantly higher among patients living in Nuuk for all process indicators compared with patients from the remaining parts of Greenland. The prevalence of asthma in Greenland is low compared to other comparable populations and might be underestimated. Initiatives supporting increased focus on diagnosing asthma are thus warranted.

Prevalence of patients using antihypertensive medication in Greenland, and an assessment of the importance of diagnosis for the associated quality of care - a cross-sectional study.

This study aimed to estimate the age- and sex specific prevalence of patients using antihypertensive medication in Greenland, and compared the quality of care between patients with and without a diagnosis for hypertension. The study was a cross-sectional study comparing patients using antihypertensive medication in 2020 (6,629 patients) and 2021 (7,008 patients), respectively. For data from 2021, patients with a medical diagnosis code were identified. Data was obtained from the Greenlandic electronic medical record. The population of Greenland was used as background population. Quality of care was evaluated based on suggested indicators by international guidelines and goals from Steno Diabetes Centre Greenland. The prevalence of patients aged ≥20 years using antihypertensive medication had increased from 16.7% in 2020 to 17.5% in 2021. The prevalence increased by age and was higher among women compared to men. In 2021, the prevalence of patients aged ≥20 years with a medical diagnosis code for hypertension was 7.9%. The use of antihypertensive medication in Greenland is common. The associated quality of care was low. However, process indicators were significantly improved when patients had a medical diagnosis code. Future focus must be on initiating initiatives ensuring that more patients are registered with a medical diagnosis code.

Prevalence of Patients Receiving Urate-Lowering Medicine in Greenland and Denmark: A Cross-Sectional Case-Control Study.

This study estimates the age- and sex-specific prevalence of patients receiving urate-lowering therapy (ULT) in Greenland and compares the results with estimates in Denmark. Characteristics of patients receiving ULT in Greenland were compared to age- and sex-matched controls. The study was designed as a cross-sectional case−control study based on nationwide data from medical and population registers in Greenland and Denmark. The prevalence of patients receiving ULT was significantly lower in Greenland (0.55%) compared to Denmark (1.40%) (p < 0.001). In both countries, the prevalence increased with age and was higher among men compared to women. In Greenland, patients receiving ULT were more often overweight, and more frequently received blood glucose-, lipid-, and blood pressure-lowering medicine including diuretics compared to age- and sex-matched controls. The prevalence of patients receiving ULT was significantly lower in Greenland compared to Denmark. Common life-style related risk factors for hyperuricemia and gout were observed frequently among ULT-treated patients compared to controls. Along with an increasing prevalence of lifestyle-related diseases in Greenland, the prevalence of patients receiving ULT may increase in the years to come. More focus on detection and management of hyperuricemia and gout in Greenland is warranted to improve quality of health care.

The prevalence of patients treated for osteoporosis in Greenland is low compared to Denmark.

The study is a register-based cross-sectional study aiming to estimate the prevalence of treated osteoporosis in Greenland compared to Denmark and provide a description of the patients with osteoporosis in Greenland. In addition, the study estimates the incidence of hip fractures in Greenland from 2018 to 2020 among people aged 65 years or older. The overall prevalence of patients prescribed medication for osteoporosis among those aged 18 years or older was 0.56% in Greenland and 2.36% in Denmark (p < 0.001). Among those aged 50 years or older, the prevalence was 1.28% and 4.71% in Greenland and Denmark, respectively (p < 0.001). The prevalence increased to 3.41% and 11.18% among patients aged 80 years or older in Greenland and Denmark, respectively. The incidence of hip fractures in Greenland was 6.55 per 1,000 inhabitants in 2020 compared to 5.65 per 1,000 inhabitants in Denmark (NS). In conclusion, the prevalence of treated osteoporosis in Greenland was less than one in four of that of Denmark. The incidence of hip fractures was similar in Greenland than in Denmark. Hence, our findings suggest that a marked number of subjects with osteoporosis in Greenland go untreated.

Low prevalence of patients diagnosed with psoriasis in Nuuk: a call for increased awareness of chronic skin disease in Greenland.

The objective of this study was to estimate the age- and gender-specific prevalence of psoriasis in Nuuk. Furthermore, we aimed to explore the common risk factors and comorbidities for patients with psoriasis compared to an age- and gender-matched control group. The study was designed as a cross- sectional case-control study based on national high-quality data from medical and population registers in Nuuk. A total of 175 patients (0.9%) were diagnosed with psoriasis in Nuuk by January 1 January 2022, of which 79 were females and 96 were males. The prevalence of patients diagnosed with psoriasis in the adult population aged 20 years old or more in Nuuk was 1.1%. No overall gender-specific difference in prevalence was observed. Chronic diseases including diabetes, hypertension, and obstructive lung disease were observed more frequently among patients with diagnosed psoriasis (28.6%) in Nuuk compared to controls (20.9%) (p < 0.05). We found a low prevalence of patients with psoriasis in Nuuk. We speculate that the prevalence found in this study is underestimated and thus, call for increased awareness of chronic skin disease in Nuuk, Greenland. Chronic co-morbidity to psoriasis was common.

Prevalence and quality of care among patients using medication targeting obstructive lung disease: a cross-sectional study in the five regions of Greenland.

The aim of this study was to estimate the age- and gender-specific prevalence and quality of care among patients using medication targeting obstructive lung disease in the five regions of Greenland. The study was designed as a cross-sectional study. Data on patients using medication targeting obstructive lung disease was obtained from the electronically medical record used in Greenland. The prevalence was calculated using the population of Greenland as background population. The quality of care was determined using indicators proposed by international literature and the Steno Diabetes Center Greenland guidelines. The total prevalence of patients using medication targeting obstructive lung disease was 7.5%. The prevalence was significantly higher among women compared to men and differed significantly between the five regions. Smoking status, blood pressure and spirometry were registered within one/two years for 29.8%/43.2%, 29.2%/41.1% and 15.9%/26.0% of the patients, respectively. Regional differences were observed for all indicators.The use of medication targeting obstructive lung disease is common in Greenland. Yet, the quality of care was low and interventions improving the quality of care is recommended.

Prevalence of patients treated with antidepressant medicine in Greenland and Denmark: a cross-sectional study.

Depression is a mental illness affecting more than 260 million people worldwide. In Greenland, the prevalence of patients treated with antidepressant medicine (antidepressants) has not previously been investigated. The aim of this study was to estimate and compare the age- and gender-specific prevalence of patients treated with antidepressants in Greenland and Denmark. The study was a cross-sectional register study using data from population and medical registers in Greenland and Denmark. Included was 1,573 Greenlandic patients and 419,151 Danish patients treated with antidepressants, respectively. The overall prevalence of patients aged 10-89 years treated with antidepressants was 3.5% in Greenland, and 8.1% in Denmark, being significantly lower in Greenland compared to Denmark (p < 0.001). The age- and gender-specific prevalence was significantly lower for patients from Greenland compared to from Denmark. In both Greenland and Denmark, the prevalence of women receiving antidepressants was significantly higher than for men. Finally, there was regional differences in the prevalence of usage of antidepressants in Greenland. Undiagnosed depression might contribute to the lower prevalence in Greenland as well as limited access to primary healthcare.

Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in ß-Cells.

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced ß-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the ß-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. ß-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis.

AIMS: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. MATERIALS AND METHODS: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. RESULTS: GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. CONCLUSION: Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations.

The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin ß1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

Combined activity of COX-1 and COX-2 is increased in non-neoplastic colonic mucosa from colorectal neoplasia patients.

BACKGROUND: Cyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment. METHODS: Biopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts). RESULTS: Combined COX-1 and COX-2 activity was higher in CRN-pts, p = 0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium. CONCLUSIONS: In biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells.

Lysine demethylase inhibition protects pancreatic ß cells from apoptosis and improves ß-cell function.

Transcriptional changes control ß-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects ß cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate ß-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced ß-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated. These data suggest that KDMs are important regulators of inflammation-induced ß-cell dysfunction and death.

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia.

BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. METHODS: Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. CONCLUSION: In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.

Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress.

Dietary advice is the cornerstone in first-line treatment of metabolic diseases. Nutritional interventions directed at these clinical conditions mainly aim to (a) improve insulin resistance by reducing energy-dense macronutrient intake to obtain weight loss and (b) reduce fluctuations in insulin secretion through avoidance of rapidly absorbable carbohydrates. However, even in the majority of motivated patients selected for clinical trials, massive efforts using this approach have failed to achieve lasting efficacy. Less attention has been given to the role of micronutrients in metabolic diseases. Here, we review the evidence that highlights (a) the importance of iron in pancreatic beta-cell function and dysfunction in diabetes and (b) the integrative pathophysiological effects of tissue iron levels in the interactions among the beta cell, gut microbiome, hypothalamus, innate and adaptive immune systems, and insulin-sensitive tissues. We propose that clinical trials are warranted to clarify the impact of dietary or pharmacological iron reduction on the development of metabolic disorders.