Objectives  To evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality. Design  Meta-analysis of prospective cohort studies. Data sources  Electronic databases (PubMed, Embase, and Google Scholar). Selection criteria  Prospective cohort studies from general populations were included for meta-analysis if they reported adjusted relative risks with 95% confidence intervals for associations between the risk of composite cardiovascular disease, coronary heart disease, stroke, all cause mortality, and prediabetes. Review methods  Two authors independently reviewed and selected eligible studies, based on predetermined selection criteria. Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L during an oral glucose tolerance test), or raised haemoglobin A 1c (HbA 1c ) of 39-47 mmol/mol (5.7-6.4%) according to ADA criteria or 42-47 mmol/mol (6.0-6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. The relative risks of all cause mortality and cardiovascular events were calculated and reported with 95% confidence intervals. Results  53 prospective cohort studies with 1 611 339 individuals were included for analysis. The median follow-up duration was 9.5 years. Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA 1c to 39-47 mmol/mol or 42-47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality. Conclusions  Prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, or raised HbA 1c , was associated with an increased risk of cardiovascular disease. The health risk might be increased in people with a fasting glucose concentration as low as 5.6 mmol/L or HbA 1c of 39 mmol/mol.

https://www.bmj.com/content/bmj/355/bmj.i5953.full.pdf

Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis

Background. Reports on the association of prediabetes with all-cause mortality and cardiovascular mortality are inconsistent.Objective. To evaluate the risk of all-cause and cardiovascular mortality in association with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).Methods. Prospective cohort studies with data on prediabetes and mortality were included. The relative risks (RRs) of all-cause and cardiovascular mortality were calculated and reported with 95% confidence intervals (95% CIs).Results. Twenty-six studies were included. The risks of all-cause and cardiovascular mortality were increased in participants with prediabetes defined as IFG of 110–125 mg/dL (IFG 110) (RR 1.12, 95% CI 1.05–1.20; and RR 1.19, 95% CI 1.05–1.35, respectively), IGT (RR 1.33, 95% CI 1.24–1.42; RR 1.23, 95% CI 1.11–1.36, respectively), or combined IFG 110 and/or IGT (RR 1.21, 95% CI 1.11–1.32; RR 1.21, 95% CI 1.07–1.36, respectively), but not when IFG was defined as 100–125 mg/dL (RR 1.07, 95% CI 0....

Associations of prediabetes with all-cause and cardiovascular mortality: A meta-analysis

The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis. We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31–35 kg/m2 and 28–31 kg/m2 (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m2). In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.

https://link.springer.com/content/pdf/10.1007%2Fs00125-016-4162-6.pdf

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies.

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. SIGNIFICANCE: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.This article is highlighted in the In This Issue feature, p. 1.

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Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the Hippo pathway

The MAPK/ERK pathway has a critical role in PNS development. It is required for Schwann cell (SC) differentiation and myelination; sustained embryonic MAPK/ERK activation in SCs enhances myelin growth overcoming signals that normally end myelination. Excess activation of this pathway can be maladaptive as in adulthood acute strong activation of MAPK/ERK has been shown to cause SC dedifferentiation and demyelination. We used a mouse model (including male and female animals) in which the gain-of-function MEK1DD allele produces sustained MAPK/ERK activation in adult SCs, and we determined the impact of such activation on nerve repair. In the uninjured nerve, MAPK/ERK activation neither impaired myelin nor reactivated myelination. However, in the injured nerve it was detrimental and resulted in delayed repair and functional recovery. In the early phase of injury, the rate of myelin clearance was faster. Four weeks following injury, when nerve repair is normally advanced, myelinated axons of MEK1DD mutants demonstrated higher rates of myelin decompaction, a reduced number of Cajal bands. and decreased internodal length. We noted the presence of abnormal Remak bundles with long SCs processes and reduced numbers of C-fibers/Remak bundle. Both the total number of regenerating axons and the intraepidermal nerve fiber density in the skin were reduced. Sustained activation of MAPK/ERK in adult SCs is therefore deleterious to successful nerve repair, emphasizing the differences in the signaling processes coordinating nerve development and repair. Our results also underline the key role of SCs in axon regeneration and successful target reinnervation.SIGNIFICANCE STATEMENT The MAPK/ERK pathway promotes developmental myelination and its sustained activation in SCs induced continuous myelin growth, compensating for the absence of essential myelination signals. However, the strength of activation is fundamental because acute strong induction of MAPK/ERK in adulthood induces demyelination. What has been unknown is the effect of a mild but sustained MAPK/ERK activation in SCs on nerve repair in adulthood. This promoted myelin clearance but led to abnormalities in nonmyelinating and myelinating SCs in the later phases of nerve repair, resulting in slowed axon regeneration, cutaneous reinnervation, and functional recovery. Our results emphasize the distinct role of the MAPK/ERK pathway in developmental myelination versus remyelination and the importance of signaling between SCs and axons for successful axon regeneration.

https://www.jneurosci.org/content/jneuro/38/3/679.full.pdf

Sustained MAPK/ERK Activation in Adult Schwann Cells Impairs Nerve Repair.

OBJECTIVES Diabetes and obesity each increases mortality, but recent papers have shown that lean Asian persons were at greater risk for mortality than were obese persons. The objective of this study is to determine whether an interaction exists between body mass index (BMI) and diabetes, which can modify the risk of death by cardiovascular disease (CVD). METHODS Subjects who were over 20 years of age, and who had information regarding BMI, past history of diabetes, and fasting blood glucose levels (n=16 048), were selected from the Korea Multi-center Cancer Cohort study participants. By 2008, a total of 1290 participants had died; 251 and 155 had died of CVD and stroke, respectively. The hazard for deaths was calculated with hazard ratio (HR) and 95% confidence interval (95% CI) by Cox proportional hazard model. RESULTS Compared with the normal population, patients with diabetes were at higher risk for CVD and stroke deaths (HR, 1.84; 95% CI, 1.33 to 2.56; HR, 1.82; 95% CI, 1.20 to 2.76; respectively). Relative to subjects with no diabetes and normal BMI (21 to 22.9 kg/m(2)), lean subjects with diabetes (BMI <21 kg/m(2)) had a greater risk for CVD and stroke deaths (HR, 2.83; 95% CI, 1.57 to 5.09; HR, 3.27; 95% CI, 1.58 to 6.76; respectively), while obese subjects with diabetes (BMI ≥25 kg/m(2)) had no increased death risk (p-interaction <0.05). This pattern was consistent in sub-populations with no incidence of hypertension. CONCLUSIONS This study suggests that diabetes in lean people is more critical to CVD deaths than it is in obese people.

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En-Joo Jung

Papers

Interaction of Body Mass Index and Diabetes as Modifiers of Cardiovascular Mortality in a Cohort Study

Abstract 4675: Alcohol consumption and mortality in the Korean Multi-center Cancer Cohort (KMCC) Study