The gastrointestinal tract - the largest endocrine network in human physiology - orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in ...understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies - GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors - for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut-renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut-renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.
Stress-related hyperglycaemia (SHG) is commonly seen in acutely ill patients and has been associated with poor outcomes in many studies performed in different acute care settings. We aimed to review ...the available evidence describing the associations between SHG and different outcomes in acutely ill patients admitted to an ICU. Study designs, populations, and outcome measures used in observational studies were analysed.
We conducted a systematic scoping review of observational studies following the Joanna Briggs methodology. Medline, Embase, and the Cochrane Library were searched for publications between January 2000 and December 2015 that reported on SHG and mortality, infection rate, length of stay, time on ventilation, blood transfusions, renal replacement therapy, or acquired weakness.
The search yielded 3,063 articles, of which 43 articles were included (totalling 536,476 patients). Overall, the identified studies were heterogeneous in study conduct, SHG definition, blood glucose measurements and monitoring, treatment protocol, and outcome reporting. The most frequently reported outcomes were mortality (38 studies), ICU and hospital length of stay (23 and 18 studies, respectively), and duration of mechanical ventilation (13 studies). The majority of these studies (40 studies) compared the reported outcomes in patients who experienced SHG with those who did not. Fourteen studies (35.9%) identified an association between hyperglycaemia and increased mortality (odds ratios ranging from 1.13 to 2.76). Five studies identified hyperglycaemia as an independent risk factor for increased infection rates, and one identified it as an independent predictor of increased ICU length of stay.
SHG was consistently associated with poor outcomes. However, the wide divergences in the literature mandate standardisation of measuring and monitoring SHG and the creation of a consensus on SHG definition. A better comparability between practices will improve our knowledge on SHG consequences and management.
To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease ...(CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related.
Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC.
Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (β-coefficient: 0.02 (0.02, 0.03), p = 3 × 10
); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)).
Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.
Malignant tumors are often multifactorial. Epidemiological studies have shown that hyperglycemia raises the prevalence and mortality of certain malignancies, like breast, liver, bladder, pancreatic, ...colorectal, endometrial cancers. Hyperglycemia can promote the proliferation, invasion and migration, induce the apoptotic resistance and enhance the chemoresistance of tumor cells. This review focuses on the new findings in the relationship between hyperglycemia and tumor development.
To investigate if early electronic identification and bedside management of inpatients with diabetes improves glycemic control in noncritical care.
We investigated a proactive or early intervention ...model of care (whereby an inpatient diabetes team electronically identified individuals with diabetes and aimed to provide bedside management within 24 h of admission) compared with usual care (a referral-based consultation service). We conducted a cluster randomized trial on eight wards, consisting of a 10-week baseline period (all clusters received usual care) followed by a 12-week active period (clusters randomized to early intervention or usual care). Outcomes were adverse glycemic days (AGDs) (patient-days with glucose <4 or >15 mmol/L <72 or >270 mg/dL) and adverse patient outcomes.
We included 1,002 consecutive adult inpatients with diabetes or new hyperglycemia. More patients received specialist diabetes management (92% vs. 15%,
< 0.001) and new insulin treatment (57% vs. 34%,
= 0.001) with early intervention. At the cluster level, incidence of AGDs decreased by 24% from 243 to 186 per 1,000 patient-days in the intervention arm (
< 0.001), with no change in the control arm. At the individual level, adjusted number of AGDs per person decreased from a mean 1.4 (SD 1.6) to 1.0 (0.9) days (-28% change 95% CI -45 to -11,
= 0.001) in the intervention arm but did not change in the control arm (1.8 2.0 to 1.5 1.8, -9% change -25 to 6,
= 0.23). Early intervention reduced overt hyperglycemia (55% decrease in patient-days with mean glucose >15 mmol/L,
< 0.001) and hospital-acquired infections (odds ratio 0.20 95% CI 0.07-0.58,
= 0.003).
Early identification and management of inpatients with diabetes decreased hyperglycemia and hospital-acquired infections.
The posttranslationally modified forms of Hb A1a, A1b, and A1c, Can be separated and quantified by the techniques of chromatography; Their levels reflect the time-averaged blood glucose for 6 to 8 ...weeks, It is a good index of the glycemic status of the blood, so to speak.
Measurement of glycated hemoglobin (HbA
) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute ...events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA
testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA
measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.
Abstract Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture ...healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10 days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo . In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.
Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function
. Currently, there are no therapies proven to prevent beta cell loss and some, ...namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes
. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion
. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of many diseases. However, ...intergenerational effects of this environmental information remains poorly understood. Here, using a C57BL/6 mouse model of restraint stress, we show that offspring of stressed fathers exhibit hyperglycemia due to enhanced hepatic gluconeogenesis and elevated expression of PEPCK. Mechanistically, we identify an epigenetic alteration at the promoter region of the Sfmbt2 gene, a maternally imprinted polycomb gene, leading to a downregulation of intronic microRNA-466b-3p, which post-transcriptionally inhibits PEPCK expression. Importantly, hyperglycemia in F1 mice is reversed by RU486 treatment in fathers, and dexamethasone administration in F0 mice phenocopies the roles of restraint stress. Thus, we provide evidence showing the effects of paternal psychological stress on the regulation of glucose metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers.
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•Paternal psychological stress promotes hepatic gluconeogenesis in offspring•Reduced expression of miR-466b-3p increases PEPCK protein contents in stress-F1 mice•Promoter hypermethylation of the Sfmbt2 gene leads to downregulation of miR-466b-3p•Paternal elevated glucocorticoids contribute to hyperglycemia in offspring
Using a mouse model of restraint stress, Wu et al. uncover the intergenerational effects of paternal psychological stress on glucose metabolism in offspring. Paternal stress epigenetically downregulates miR-466b-3p expression, leading to increased PEPCK expression and hepatic gluconeogenesis in hyperglycemic F1 mice.
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