Transitioning from intravenous to subcutaneous insulin in the medical intensive care unit.

BACKGROUND: There is a paucity of studies on transitions from IV insulin infusion (IVII) to subcutaneous (SC) insulin in the medical ICU (MICU). METHODS: We conducted a retrospective study of patients admitted to the Cleveland Clinic MICU from June 2013 to January 2014 who received IVII. We compared blood glucose (BG) control between 3 cohorts based on timing of basal insulin dose: (1) NB (no basal), (2) IB (incorrect basal), (3) CB (correct basal) at 5 time points post-IVII discontinuation (1, 4, 8, 12, and 24h). Insulin doses used for transitioning were compared with 80% of estimated 24h IVII total. Analysis was done using chi-square, ANOVA and t-tests. RESULTS: There were 269 patients (NB 166, IB 45, CB 58), 55% male with a mean age 58±16years. 103 patients (38%) had a transition attempted (IB 21%, CB 17%). The NB cohort had better BG than the IB cohort at all time points (p<0.001) but also lower HbA1c, prior DM diagnosis and home insulin use (p<0.001). IB and CB did not have significantly different BG with mean BG>180mg/dL at 4/5 time intervals. However, the dose of basal insulin used was less than 80% of estimated 24h IVII total (IB 21.4 vs 49.6U, CB 25vs 57.1U). Despite this, 15% of patients in the IB cohort and 24% of patients in the CB had hypoglycemic events. CONCLUSION: The low rates of IV to SC insulin transitions raises the question of challenges to transitions.

Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure.

Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased beta-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and G alpha(s) expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to beta-receptor blockade.

Hierarchy of polymorphic variation and desensitization permutations relative to beta 1- and beta 2-adrenergic receptor signaling.

Agonist-promoted desensitization of G-protein-coupled receptors results in partial uncoupling of receptor from cognate G-protein, a process that provides for rapid adaptation to the signaling environment. This property plays important roles in physiologic and pathologic processes as well as therapeutic efficacy. However, coupling is also influenced by polymorphic variation, but the relative impact of these two mechanisms on signal transduction is not known. To determine this we utilized recombinant cells expressing the human beta(1)-adrenergic receptor (beta(1)AR) or a gain-of-function polymorphic variant (beta(1)AR-Arg(389)), and the beta(2)-adrenergic receptor (beta(2)AR) or a loss-of-function polymorphic receptor (beta(2)AR-Ile(164)). Adenylyl cyclase activities were determined with multiple permutations of the possible states of the receptor: genotype, basal, or agonist stimulated and with or without agonist pre-exposure. For the beta(1)AR, the enhanced function of the Arg(389) receptor underwent less agonist-promoted desensitization compared with its allelic counterpart. Indeed, the effect of polymorphic variation on absolute adenylyl cyclase activities was such that desensitized beta(1)AR-Arg(389) signaling was equivalent to non-desensitized wild-type beta(1)AR; that is, the genetic component had as much impact as desensitization on receptor coupling. In contrast, the enhanced signaling of wild-type beta(2)AR underwent less desensitization compared with beta(2)AR-Ile(164), thus the heterogeneity in absolute signaling was markedly broadened by this polymorphism. Inverse agonist function was not affected by polymorphisms of either subtype. A general model is proposed whereby up to 10 levels of signaling by G-protein-coupled receptors can be present based on the influences of desensitization and genetic variation on coupling.

Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure.

BACKGROUND: Exercise performance in patients with congestive heart failure is partially dependent on cardiac beta1-adrenergic receptor (beta1AR) function. There are 2 common polymorphisms of the beta1AR gene that alter the encoded amino acids at positions 49 (Ser or Gly) and 389 (Gly or Arg) and alter receptor function in vitro. Their relevance to modification of cardiac function in heart failure is not known. METHODS: Exercise testing was performed in 263 patients with idiopathic or ischemic cardiomyopathy (left ventricular ejection fraction approximately 25%). Potential associations were sought between beta1AR genotypes and the primary outcome variables of peak oxygen consumption (VO2), heart rate response, and exercise time. RESULTS: The major determinants of exercise capacity were the polymorphisms at position 389, where patients homozygous for Gly389 had significantly lower peak VO2 compared with those with Arg389 (14.5 +/- 0.6 vs 17.7 +/- 0.4 mL/kg/min, P =.006), despite similar clinical characteristics including left ventricular ejection fraction. Consistent with a gene dose-response, heterozygosity was associated with an intermediate response (16.9 +/- 0.6 mL/kg/min, P <.05). When position 49 genotypes were included, a graded relationship between the 5 2-locus haplotypes and VO2 was found. Two haplotypes displayed the most divergent peak VO2: homozygous Gly389/Ser49, and homozygous Arg389/Gly49 carriers (14.4 +/- 0.5 vs 18.2 +/- 0.8 mL/kg/min, P =.001). Genotype did not predict the heart rate response. The above results were independent of beta-blocker or other medication use, left ventricular ejection fraction, beta2AR genotype, or other demographic and clinical characteristics. CONCLUSION: beta1AR polymorphisms are a significant determinant of exercise capacity in patients with congestive heart failure. Early identification, by genetic testing for these polymorphisms, of heart failure patients at risk for development of depressed exercise capacity may be useful for initiation of specific therapy tailored to genotype.

Amino acid 49 polymorphisms of the human beta1-adrenergic receptor affect agonist-promoted trafficking.

The signaling impact of a human beta1-adrenergic receptor (beta1 AR) polymorphism at residue 49 of the aminoterminus (Ser-to-Gly substitution) was studied by recombinantly expressing each receptor. The two receptors displayed identical agonist and antagonist binding affinities. Furthermore, basal and agonist-stimulated adenylyl cyclase activities were the same for these receptors as assessed in both cell types. Although short-term agonist exposure resulted in similar degrees of receptor internalization, long-term agonist-promoted downregulation was greater for Gly49 compared with Ser49. The Gly49 receptor underwent a 24 +/- 3% loss of receptor density after exposure to isoproterenol for 18 h, whereas Ser49 underwent no such loss. In studies in which receptor synthesis was inhibited, agonist-promoted downregulation for Gly49 was 55 +/- 3% compared with 36 +/- 5% for Ser49. In the absence of agonist, degradative turnover of each receptor was the same. Immunoblotting revealed that some of the Ser49 receptor exists as a highly N-glycosylated form (approximately 105-kD molecular mass), which is not present with Gly49. Thus the phenotype of the Gly49 polymorphic receptor is that of wild-type coupling with enhanced agonist-promoted downregulation, which is associated with altered N-glycosylation. Based on this cellular phenotype, the beta1 AR Gly49 polymorphism may impart a beneficial effect in chronic heart failure.