Improving Intravenous and Subcutaneous Insulin Overlap During Treatment of Diabetic Ketoacidosis: A Quality Improvement Project.

Objective: To reduce the frequency of insufficient overlap of intravenous (IV) and subcutaneous (SC) insulin during the treatment of diabetic ketoacidosis (DKA) as a quality improvement project. Patients and Methods: Rates of insufficient IV and SC insulin overlap (< 2-hour overlap, SC insulin given after IV insulin discontinuation, or no SC insulin given after IV insulin discontinuation) were assessed in adults with DKA treated with IV insulin at a large tertiary care referral center in Rochester, Minnesota, from July 1, 2021, to March 15, 2023. After a preintervention analysis period, an electronic medical record-based best practice advisory was introduced to notify hospital providers discontinuing IV insulin if SC long-acting insulin had not been given in the previous 2-6 hours. Demographic characteristics and clinical outcomes before and after intervention were compared. Results: A total of 352 patient encounters were included (251 in the preintervention phase and 101 in the postintervention phase). The rate of insufficient IV to SC insulin overlap decreased from (88 of 251) 35.1% before intervention to (20 of 101) 19.8% after intervention (P=.005). The rate of posttransition hypoglycemia (<70 mg/dL; to convert to mmol/L, multiply by 0.0259) decreased from (27 of 251) 10.7% to (4 of 101) 4% after intervention (P=.04). Rates of posttransition hyperglycemia (>250 mg/dL), rebound DKA, length of hospital stay, and duration of IV insulin therapy were similar before and after intervention. Conclusion: Using quality improvement methodology, the rates of insufficient IV to SC insulin overlap during treatment of DKA in a large tertiary care referral center were measured and reduced through an electronic medical record-based best practice advisory targeting hospital providers.

Adrenal Hemorrhage: A Comprehensive Analysis of a Heterogeneous Entity-Etiology, Presentation, Management, and Outcomes.

OBJECTIVE: To investigate the etiology, presentation, management, and outcomes of patients with adrenal hemorrhage (AH). PATIENTS AND METHODS: Longitudinal study of consecutive adult patients with radiologically confirmed AH (January 1, 2017, through December 31, 2021). RESULTS: Of the 363 patients with AH (median age, 62 years [interquartile range (IQR, 52-70 years]; 128 women [35%]), 338 (93%) had unilateral AH and 25 (7%) had bilateral AH. It was discovered incidentally in 152 patients (42%) and during the evaluation of trauma in 103 (28%), abdominal/back pain in 90 (25%), critical illness in 13 (4%), and symptoms of adrenal insufficiency in 5 (1%). Etiologies included postoperative complications in 150 patients (41%), trauma in 107 (30%), coagulopathy in 22 (6%), anticoagulant/antiplatelet therapy in 39 (11%), adrenal neoplasm in 22 (6%), and sepsis in 11, (3%). Overall, 165 patients (46%) were hospitalized, and no deaths occurred due to AH. Median (IQR) baseline AH size was 34 mm (24-40 mm) on the right and 29 mm (22-37 mm) on the left. Among 246 patients with follow-up imaging, AH resolution was complete in 155 (63%) and incomplete in 74 (30%) at a median of 15 months (IQR, 6-31 months). Patients with bilateral AH were more likely to have underlying coagulopathy (44% vs 3%) and to develop primary adrenal insufficiency (72% vs 0%) than those with unilateral AH (P<.001). CONCLUSION: Often, AH presents as an incidental unilateral lesion with normal adrenal function, commonly attributed to postoperative complications or trauma. In contrast, bilateral AH is rare and typically linked to underlying coagulopathy, with primary adrenal insufficiency developing in most patients.

Kidney function in patients with adrenal adenomas: A single-center retrospective cohort study.

OBJECTIVE: Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD), however factors associated with CKD are unknown. We aimed to identify the factors associated with CKD and assess the impact of adrenalectomy on kidney function in patients with NFA or MACS. DESIGN: Single-center cohort study of patients with NFA and MACS, 1999-2020. METHODS: MACS was diagnosed based on post-dexamethasone cortisol (DST) ≥ 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and post-adrenalectomy delta eGFR. RESULTS: Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 ml/min/1.73m2, p < 0.001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, post adrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow up. Factors associated with increased eGFR were younger age, lower pre-adrenalectomy eGFR and longer follow-up period. CONCLUSION: DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Both patients with MACS and NFA demonstrate an increase in eGFR post-adrenalectomy, especially younger patients with lower eGFR pre-adrenalectomy.

Etiology, morphology, and outcomes of adrenal calcifications in 540 adult patients-a retrospective single-center study.

Sparse data are available on the etiology, morphology, clinical presentation, and outcomes of adrenal calcification. In this single-center retrospective study of 540 consecutive patients (median age 65 years, 45% women) with adrenal calcification on computed tomography (December 2017 to January 2021), most were discovered incidentally (472, 87%). The commonest etiology was idiopathic (389, 72%), followed by the adrenal tumor (113, 21%), hemorrhage (29, 5%), and infiltrative disease (7, 1%). Calcified adrenal tumors were predominantly benign (92, 81%) and primarily adenomas (63, 69%), whereas the most common calcified adrenal malignancy (16, 18%) was metastasis (12, 67%). Calcification (unilateral 94%, bilateral 6%) morphology varied from punctate (313, 58%) to coarse (165, 30%), linear/curvilinear (46, 9%), and rim-like (16, 3%). In summary, adrenal calcifications are usually incidentally discovered unilateral, punctate, or coarse lesions of unclear etiology. Most calcified adrenal tumors are benign and <20% malignant or pheochromocytomas.

Evolution of insulin at the edge of foldability and its medical implications.

Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and ß-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue TyrB24, impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric TyrB24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of TyrB24 is similar to that of PheB24, adjoining core cystine B19-A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ∼20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of PheB24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para-hydroxyl group of TyrB24 hinders pairing of cystine B19-A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge-excluded due to ß-cell dysfunction-suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein's fitness landscape underlies both a rare monogenic syndrome and "diabesity" as a pandemic disease of civilization.

Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes.

Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus. Diabetes (mostly type 2 diabetes mellitus, T2DM) and hyperglycemia are among the major comorbidities in patients with COVID-19 leading to poor outcomes. Reports show that patients with diabetes and COVID-19 are at an increased risk for developing severe complications including acute respiratory distress syndrome, multi-organ failure, and death. Here we explore potential mechanistic links that could explain the observed higher morbidity and mortality in this patient population. Patients with T2DM have an underlying increased level of inflammation associated with obesity and insulin resistance in addition to other comorbidities including hypertension, obesity, cardiovascular disease, dyslipidemia, and being older. We review evidence that T2DM with hyperglycemia are among factors that lead to elevated expression of angiotensin-converting enzyme 2 (ACE2) in lungs and other tissues; ACE2 is the cellular "receptor" and port of viral entry. The preexisting chronic inflammation with augmented inflammatory response to the infection and the increasing viral load leads to extreme systemic immune response ("cytokine storm") that is strongly associated with increased severity of COVID-19. Based on the available evidence, it is recommended by a panel of experts that safe but stringent control of blood glucose, blood pressure, and lipids be carried out in patients with T2DM, measures that could potentially serve to decrease the severity of COVID-19 should these patients contract the viral infection. Once the infection occurs, then attention should be directed to proper glycemic control with use of insulin and frequent monitoring of blood glucose levels.

Challenging Issues in the Management of Cardiovascular Risk Factors in Diabetes During the COVID-19 Pandemic: A Review of Current Literature.

The COVID-19 outbreak was declared a pandemic on March 2020. Many patients with SARS-CoV-2 infection have underlying chronic medical conditions such as diabetes, cardiovascular disease (CVD), and hypertension. Patient-related outcomes are worse if there are associated comorbidities. We do not have enough evidence regarding the most appropriate management of patients with diabetes during COVID-19 infection. Insulin resistance and CVD together increase the inflammatory state of the body, which can contribute to and perhaps mediate the increase of COVID-19 severity. Hence, in addition to management of dysglycemia, other CVD risk factors should be targeted. We explore the possible pathophysiologic links between diabetes and COVID-19 and discuss various options to treat dysglycemia, hypertension, and dyslipidemia in the era of COVID-19.

Glucocorticoid-Induced Fatty Liver Disease.

Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of very-low-density lipoprotein synthesis and secretion into the circulation and inhibition of ß-oxidation of fatty acids. Role of 11ß-hydroxysteroid dehydrogenases-1 and -2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.

"Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.

Globular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e. a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state. Here, we exploited the mutant proinsulin syndrome (a major cause of permanent neonatal-onset diabetes mellitus) to investigate whether toxic misfolding poses an evolutionary constraint. Our experiments focused on an invariant aromatic motif (PheB24-PheB25-TyrB26) with complementary roles in native self-assembly and receptor binding. A novel class of mutations provided evidence that insulin can bind to the insulin receptor (IR) in two different modes, distinguished by a "register shift" in this motif, as visualized by molecular dynamics (MD) simulations. Register-shift variants are active but defective in cellular foldability and exquisitely susceptible to fibrillation in vitro Indeed, expression of the corresponding proinsulin variant induced endoplasmic reticulum stress, a general feature of the mutant proinsulin syndrome. Although not present among vertebrate insulin and insulin-like sequences, a prototypical variant ([GlyB24]insulin) was as potent as WT insulin in a rat model of diabetes. Although in MD simulations the shifted register of receptor engagement is compatible with the structure and allosteric reorganization of the IR-signaling complex, our results suggest that this binding mode is associated with toxic misfolding and so is disallowed in evolution. The implicit threat of proteotoxicity limits sequence variation among vertebrate insulins and insulin-like growth factors.

SGLT-2 inhibitors as promising therapeutics for non-alcoholic fatty liver disease: pathophysiology, clinical outcomes, and future directions.

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major expanding national and international health problem. Despite numerous investigations using a variety of therapeutic agents, the positive result on any single medication has not been established enough to gain widespread approval. This is in part related to concerns regarding side effects of agents, but is also related to the complex etiology of NAFLD. An often discussed question has been whether insulin resistance that is frequently present in those with NAFLD is a cause of NAFLD or is merely associated with the condition. Nevertheless, it is clear that a very high proportion of patients with NAFLD are obese, have elements of metabolic syndrome, or have type 2 diabetes (T2DM). Also, much progress has been made toward a better understanding of the pathophysiology of NAFLD. Life-style interventions resulting in weight loss remain the foundation for the prevention and treatment of NAFLD. In addition, agents such as Vitamin E and pioglitazone as well as other glycemia-lowering agents including Glucagon Like Peptide-1 (GLP-1) receptor agonists and Sodium Glucose Contransporter-2 inhibitors (SGLT-2i(s)) exhibit positive effects on the clinical course of NAFLD. This narrative review summarizes the current understanding of the diagnosis, epidemiology, and pathophysiology of NAFLD and specifically focuses on the efficacy of SGLT2i(s) as a potentially promising group of agents for the management of patients with NAFLD.

Disturbances in Insulin-Glucose Metabolism in Patients With Advanced Renal Disease With and Without Diabetes.

CONTEXT: Use of insulin in patients with diabetes and advanced chronic kidney disease (CKD; stages 4 to 5) is challenging and shows great variability among individuals. We explored the mechanisms underlying this variability. EVIDENCE ACQUISITION: PubMed was searched for articles in English from 1960 to 2018 for advanced CKD and diabetes, glucose and insulin metabolism, insulin clearance, secretion and resistance, plasma insulin concentration, glycemic control, hypoglycemia, insulin dosage, and continuous glucose monitoring (CGM) in CKD. EVIDENCE SYNTHESIS: The evidence shows that in most patients the daily dose of insulin needs to be significantly reduced with a high degree of variability; in some the dose remains unchanged, and rarely it is increased. The premise that the marked reduction in insulin requirement is essentially attributable to decreased insulin clearance by kidneys leading to prolongation of its plasma half-life, elevated blood insulin concentration, and hypoglycemia is not entirely correct. Other factors including decreases in food intake, insulin secretion, insulin clearance by peripheral tissues, and renal gluconeogenesis play important roles. There is also heightened resistance to insulin due to metabolic acidosis, uremic toxins, inflammatory state, and vitamin D deficiency. Importantly, the magnitude of changes in each of these factors varies between individuals with the same degree of CKD. CONCLUSIONS: In the presence of diabetes with advanced CKD, the insulin regimen should be individualized based on knowledge of the daily glucose patterns. The use of CGM is promising for safer glycemic control in patients with advanced CKD and diabetes and helps prevent extremes of hypoglycemia and hyperglycemia.

Correlation Between Cut-off Level of Tissue Transglutaminase Antibody and Marsh Classification.

BACKGROUND Duodenal biopsy is required for diagnosis of celiac disease in adults, although some studies have suggested adequate accuracy of serology alone. OBJECTIVE: We aimed to assess the correlation between anti-tissue transglutaminase (tTG) titer and pathological findings and to define the specific level of tTG for predicting celiac disease in adults without the need for biopsy sampling. METHODS This descriptive study was done on 299 participants. The tTG titer and pathological findings of duodenal biopsy samples were used for this study. Analysis of Receiver operating characteristic (ROC) curve was used to find a cut-off point of anti-tTG antibody for mucosal atrophy. RESULTS Mean tTG titers was significantly higher in patients graded as Marsh III≥ 3 (p=0.023). ROC curve analysis showed 89.1% sensitivity for cut-off point≥76.5 IU/mL of anti-tTG. For Marsh≥ II, specificity was 28% and positive predictive value was 91%.CON CLUSION There is a linear correlation between increasing tTG level and Marsh I to III. Specificity of tTG titer more than 200 was 100% for Marsh >2.