The time is now for new, lower diabetes diagnostic thresholds.

Current thresholds for diagnosing diabetes are outdated and do not represent advancements in disease understanding or ability to impact course. Today, evidence supports intervening earlier along the disease continuum to mitigate transition to frank disease and delay/reduce adverse clinical outcomes. We believe it is time for lower diabetes diagnostic criteria.

The Diabetes Syndrome - A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms.

The four basic pathophysiologic mechanisms which damage the ß-cell within diabetes (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance [IR]) also contribute to cell and tissue damage and elevate the risk of developing all typical diabetes-related complications. Genetic susceptibility to damage from abnormal external and internal environmental factors has been described including inflammation and IR. All these mechanisms can promote epigenetic changes, and in total, these pathophysiologic mechanisms interact and react with each other to cause damage to cells and tissues ultimately leading to disease. Importantly, these pathophysiologic mechanisms also serve to link other common conditions including cancer, dementia, psoriasis, atherosclerotic cardiovascular disease (ASCVD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). The "Diabetes Syndrome", an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions. Recognizing the association of the conditions within the Diabetes Syndrome due to common pathophysiologies has the potential to provide both benefit to the patient (eg, prevention, early detection, precision medicine) and to the advancement of medicine (eg, driving education, research, and dynamic decision-based medical practice).

Diabetes and Psoriasis: Different Sides of the Same Prism.

Diabetes and psoriasis are prevalent conditions with a spectrum of serious adverse outcomes. Both diseases are common comorbidities for each other, and diabetes is considered as a risk factor for psoriasis and vice versa. However, it is our contention that these diseases are not merely comorbidities of each other but rather share common underlying pathophysiologies (ie, genes and epigenetic changes, inflammation, abnormal environment, and insulin resistance) that drive disease. As such, they can be viewed as facets of the same prism. Genes can cause or permit susceptibility to damage from abnormal external and internal environmental factors, inflammation, and insulin resistance which can also drive epigenetic changes. These co-existing mechanisms act in a vicious cycle over time to potentiate cell and tissue damage to ultimately drive disease. Viewing diabetes and psoriasis through the same prism suggests potential for therapies that could be used to treat both conditions. Although additional controlled trials and research are warranted, we believe that our understanding of the overlapping pathophysiologies continues to grow, so too will our therapeutic options.

Evaluation of clinical outcomes with alvimopan in clinical practice: a national matched-cohort study in patients undergoing bowel resection.

OBJECTIVE: To evaluate in-hospital clinical outcomes after open and laparoscopic bowel resection (BR) with or without alvimopan treatment. BACKGROUND: Delayed return of gastrointestinal function after BR may be associated with greater postoperative morbidity and increased hospital length of stay (LOS). In clinical trials, alvimopan--a peripherally acting µ-opioid receptor antagonist--accelerated gastrointestinal recovery after open BR. METHODS: A retrospective matched-cohort study (NCT01150760) was conducted using a national inpatient database. Each alvimopan patient was exact matched (surgical procedure, surgeon specialty) and propensity score matched (baseline characteristics) to a nonalvimopan BR patient. Outcomes included gastrointestinal and other morbidity (cardiovascular, pulmonary, infection, cerebrovascular, thromboembolic); mortality; readmission rate; and intensive care unit (ICU) stay (intent-to-treat [ITT] population). Postoperative LOS and estimated cost were also compared (modified ITT population). RESULTS: Each cohort included 3525 ITT patients with similar baseline characteristics. Gastrointestinal (29.8% vs 35.7%) and other morbidity (cardiovascular [19.4% vs 24.0%], pulmonary [7.3% vs 10.5%], infectious [9.6% vs 11.8%], thromboembolic [1.2% vs 2.1%]), mortality (0.4% vs 1.0%), and mean ICU stay (0.3 vs 0.6 days) were lower in the alvimopan group (P ≤ 0.003 for each). Postoperative LOS and estimated direct cost were lower for all alvimopan patients and after laparoscopic and open BR (LOS: -1.1, -0.8, and -1.8 days respectively; cost: -$2345, -$1382, and -$3218, respectively; P ≤ 0.0008 for each). CONCLUSIONS: On average, alvimopan-treated patients had a lower incidence of mortality and most incidents of morbidities. Length of stay, ICU use, and estimated cost were also lower with comparable readmissions. These results in patients outside the clinical trial setting include laparoscopic colectomy and demonstrate a potential association between acceleration of gastrointestinal recovery and improved early postoperative outcomes.

Structural and functional properties of CCN proteins.

The CCN family currently comprises six members (CCN1-6) that regulate diverse cell functions, including mitogenesis, adhesion, apoptosis, extracellular matrix (ECM) production, growth arrest, and migration. These properties can result in a multiplicity of effects during development, differentiation, wound healing, and disease states, such as tumorigenesis and fibrosis. CCN proteins have emerged as major regulators of chondrogenesis, angiogenesis, and fibrogenesis. CCN proteins are mosaic in nature and consist of up to four structurally conserved modules, at least two of which are involved in binding to cell surfaces via molecules that include integrins, heparan sulfate proteoglycans, and low-density lipoprotein receptor-related protein. CCN proteins use integrins as signal transducing receptors to regulate context-dependent responses in individual cell types. The involvement of integrins in mediating CCN signaling allows for considerable plasticity in response because some effects are specific for certain integrin subtypes and integrin signaling is coordinated with other signaling pathways in the cell. In addition to their own biological properties, CCN proteins regulate the functions of other bioactive molecules (e.g., growth factors) via direct binding interactions. CCN molecules demonstrate complex multifaceted modes of action and regulation and have emerged as important matricellular regulators of cell function.

Connective tissue growth factor (CTGF/CCN2) in hepatic fibrosis.

Connective tissue growth factor (CTGF/CCN2) is a highly profibrogenic molecule which is overexpressed in many fibrotic lesions, including those of the liver. CTGF/CCN2 is transcriptionally activated by transforming growth factor-beta (TGF-beta) and appears to mediate some of the extracellular matrix (ECM)-inducing properties that have been previously attributed to TGF-beta. CTGF/CCN2 and TGF-beta stimulate connective tissue cell proliferation and ECM synthesis in vitro and exhibit shared fibrogenic and angiogenic properties in vivo. In fibrotic liver, CTGF/CCN2 mRNA and protein are produced by fibroblasts, myofibroblasts, hepatic stellate cells (HSCs), endothelial cells, and bile duct epithelial cells. CTGF/CCN2 is also produced at high levels in hepatocytes during cytochrome P-4502E1-mediated ethanol oxidation. CTGF/CCN2 expression in cultured HSCs is enhanced following their activation or stimulation by TGF-beta while exogenous CTGF/CCN2 is able to promote HSC adhesion, proliferation, locomotion, and collagen production. Collectively, these data suggest that during initiating or downstream fibrogenic events in the liver, production of CTGF/CCN2 is regulated primarily by TGF-beta in one or more cell types and that CTGF/CCN2 plays important roles in HSC activation and progression of fibrosis. This article reviews the data that support the importance of CTGF/CCN2 in hepatic fibrosis and highlights the concept that CTGF/CCN2 may represent a new therapeutic target in this disease.

Upregulation of endogenous heparin-binding EGF-like growth factor (HB-EGF) expression after intestinal ischemia/reperfusion injury.

Expression of endogenous heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a proven intestinal cytoprotective molecule, was examined in intestinal epithelial cells (IEC) in vitro, and in intestine undergoing ischemia/reperfusion (I/R) injury in vivo. In vitro, cells were exposed to anoxia for 90 min followed by reoxygenation for 1-3 h (A/R). In vivo, total midgut I/R injury was produced in rats by occlusion of the superior mesenteric artery for 30 or 90 min followed by reperfusion for 4 h. In situ hybridization and immunohistochemistry were used to study HB-EGF mRNA expression and protein production. In vitro, normal IEC had no detectable HB-EGF mRNA or protein expression. After anoxia, cells expressed HB-EGF mRNA and protein, with expression reaching a peak 2-3 h after reoxygenation. In vivo, only very low levels of HB-EGF mRNA and no detectable protein were found in normal intestine. Four hours after I/R, HB-EGF protein was detected in villous epithelia subjected to 30 min but not 90 min of ischemia, whereas HB-EGF mRNA was highly expressed after both ischemic intervals. Endogenous HB-EGF is immediately upregulated in IEC after A/R injury and in intestine after I/R injury. Thus, HB-EGF acts as an immediate early gene under these conditions.