Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been linked with diabetic ketoacidosis (DKA) (1-4). However, characteristics of "at-risk" patients are less well described. Clinical cases were collected from South Australia between December 2015 and March 2017.

Background: The aim of this study is to compare metrics specific for stress‐induced hyperglycemia (SIH) with glucose for predicting ischemic stroke outcome.Methods: This observational retrospective study (n = 300) included patients acutely hospitalized for ischemic stroke over a 3.8‐year period. We assessed the association between acute ischemic stroke outcome with the stress hyperglycemia ratio (SHR, relative increase in glycemia) and glycemic gap (GG, absolute increase in glycemia) using admission values and 5‐day maximum values, along with incidence of poor outcome above recognized clinical thresholds of glucose 10 mmol/L, SHR 1.14, and GG 2.5 mmol/L.Results: At admission, only SHR was associated with outcome after adjustment for clinical covariates (odds ratio [OR] = 2.88; 95% CI: 1.05‐7.91; P = .041), while glucose or GG were not. Admission SHR ≥ 1.14 was also an indicator of poor outcome (39.1% vs 23.4%, P = .016), but not glucose ≥10 mmol/L or GG ≥ 2.5 mmol/L. All 5‐day maximum glucose metrics were associated with outcome, as was any SHR ≥ 1.14 (40.9% vs 20.1%, P < .001) or GG ≥ 2.5 mmol/L (42.9% vs 23.4%, P = .011), but not glucose ≥10 mmol/L. Increased comorbidity was strongly associated with worse outcome (P < .001) in all models.Conclusions: SHR provided the best prognostic insight at admission to assess the relationship between SIH and ischemic stroke outcome. Absolute glucose levels failed to account for natural interpatient variation in background glycemia and provided little prognostic insight. To assess the impact of SIH, future interventional studies need to be designed using designated markers of SIH such as SHR in preference to absolute glucose.

Obstructive sleep apnea (OSA) and obesity are highly prevalent and bidirectionally associated. OSA is underrecognized, however, particularly in women. By mechanisms that overlap with those of obesity, OSA increases the risk of developing, or having poor outcomes from, comorbid chronic disorders and impairs quality of life. Using 2 illustrative cases, we discuss the relationships between OSA and obesity with type 2 diabetes, dyslipidemia, cardiovascular disease, cognitive disturbance, mood disorders, lower urinary tract symptoms, sexual function, and reproductive disorders. The differences in OSA between men and women, the phenotypic variability of OSA, and comorbid sleep disorders are highlighted. When the probability of OSA is high due to consistent symptoms, comorbidities, or both, a diagnostic sleep study is advisable. Continuous positive airway pressure or mandibular advancement splints improve symptoms. Benefits for comorbidities are variable depending on nightly duration of use. By contrast, weight loss and optimization of lifestyle behaviors are consistently beneficial.

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent “primary stress system disorders” were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the “hypocortisolemic symptom triad” of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation–genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Context Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. Objective To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. Methods A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. Results 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (μg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. Conclusion Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.