Hypoglycemia in diabetes

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.     

Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels.

Glucose modulates beta cell insulin secretion via effects on ATP-sensitive potassium (KATP) channels. To test the hypothesis that glucose exerts a similar effect on neuronal function, local glucose availability was varied in awake rats using microdialysis in the substantia nigra, the brain region with the highest density of KATP channels. 10 mM glucose perfusion increased GABA release by 111 +/- 42%, whereas the sulfonylurea, glipizide, increased GABA release by 84 +/- 20%. In contrast, perfusion of the KATP channel activator, lemakalim, or depletion of ATP by perfusion of 2-deoxyglucose with oligomycin inhibited GABA release by 44 +/- 8 and 45 +/- 11%, respectively. Moreover, the inhibition of GABA release by 2-deoxyglucose and oligomycin was blocked by glipizide. During systemic insulin-induced hypoglycemia (1.8 +/- 0.3 mM), nigral dialysate GABA concentrations decreased by 49 +/- 4% whereas levels of dopamine in striatal dialysates increased by 119 +/- 18%. We conclude that both local and systemic glucose availability influences nigral GABA release via an effect on KATP channels and that inhibition of GABA release may in part mediate the hyperexcitability associated with hypoglycemia. These data support the hypothesis that glucose acts as a signaling molecule, and not simply as an energy-yielding fuel, for neurons.     

Marital satisfaction and psychophysiological responsiveness in spouses of patients with chronic pain

The primary purpose of this study was to investigate the relationship between spouse marital satisfaction and spouse solicitousness to their physiological responsiveness during marital interactions about pain. Twenty-six couples engaged in a series of structured marital interactions about neutral and pain-related topics while monitored for skin conductance (SC) and heart rate (HR). There was strong support for the role of spouses’ marital satisfaction in predicting their physiological responsiveness. The more satisfied a spouse, the more physiologically reactive the spouses were when listening to the patient describe pain, and the less reactive when responding to it. Dissatisfied spouses demonstrated the opposite pattern. They autonomically deactivated when hearing about the pain and became reactive when responding to it. Solicitousness was not a significant predictor of the spouses’ physiological responsiveness. Block’s (1981) proposed physiological mechanism for the origin of solicitousness in spouses did not receive support. It appears that responding in any fashion may lessen the magnitude of arousal in maritally satisfied spouses, whereas dealing with pain-related topics produces unpleasant arousal in dissatisfied spouses.     

Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R(max)) of PD effects was increased, and the time to reach R(max) shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.     

Comparison of stroke volume estimation for non-steady-state and steady-state graded exercise testing

The stroke volume (SV) during exercise is an important index of the heart's functional capacity. A new method has been developed for the non-invasive estimation of exercise SV (SVex). It requires the determination of the slope for the oxygen uptake versus heart rate relationship in the steady state of graded exercise testing (GXT). The product of the slope and a constant (reciprocal of an assumed value of the arterial oxygen content) equals an estimated value for SVex. It was validated in a previous study using invasive measurements while subjects were performing steady-state GXT. However, currently the most commonly used GXT protocols are non-steady state, e.g. protocols with 1-min increment durations. We tested the hypothesis that SVex is the same for steady-state and non-steady-state GXT. A total of 30 subjects (15 males and 15 females) served as subjects for the study. Each subject performed two GXTs on different days with different increment durations - 1 and 4 min. Ventilation and gas exchange were measured with the Vacumed metabolic cart. For the male subjects, the mean (SD) SVex values for the 1- and 4-min GXTs were 155.4 (39.5) and 134.6 (27.5) ml, respectively. The corresponding values for the female subjects were 151.6 (37.6) and 134.3 (36.4) ml. Paired t-test analysis demonstrated that for both genders the mean SVex for the 1-min GXT was significantly larger than the 4-min GXT mean value (P<0.05). Hence, the commonly used 1-min GXT does not yield the same values for SVex as the steady-state GXT.     

Features of Childhood Maltreatment and Resilience Capacity in Adulthood: Results from a Large Community-Based Sample

Childhood maltreatment is consistently associated with poor outcomes. However, few epidemiological studies have examined the association between childhood maltreatment and adult resilience capacity, defined as one's perceived ability to cope successfully with challenges. This study aimed to determine associations between adult resilience capacity and specific types and features of childhood maltreatment. Participants were African American adults recruited from a public urban hospital in Atlanta, GA (N = 1,962) between 2005 and 2013. Childhood maltreatment, including witnessing domestic violence or physical, emotional, and sexual abuse, was assessed retrospectively using the Traumatic Events Inventory. Perceived resilience capacity was assessed using the Connor-Davidson Resilience Scale. Linear regressions were performed assessing the association between resilience capacity and childhood maltreatment exposure in general, as well as specific dimensions of exposure, including type, co-occurrence, and developmental timing, adjusting for covariates. Participants exposed to any maltreatment reported lower resilience capacity than unexposed peers, B = −0.38, SE = 0.04, p < .001. All maltreatment types were negatively associated with resilience capacity, even after adjusting for other lifetime trauma exposure. Only emotional abuse remained significantly associated with resilience capacity after accounting for current psychological distress, B = −0.11, SE = 0.05, p = .022. Maltreatment co-occurrence followed an inverse dose–response relationship with resilience capacity: For each additional maltreatment type, scores decreased by 0.18 units (SD = 0.02), p < .001. Finally, the developmental timing of maltreatment did not reveal any differential influences on resilience capacity. The results suggest that childhood emotional abuse and co-occurrence of maltreatment types may be particularly deleterious to adult resilience capacity.     

Residual Symptoms of Posttraumatic Stress Disorder and Alcohol Use Disorder Following Integrated Exposure Treatment Versus Coping Skills Treatment

Although some studies have demonstrated residual symptoms in patients who have participated in posttraumatic stress disorder (PTSD) treatment, no studies to date have assessed residual PTSD symptoms following treatment for comorbid alcohol use disorder (AUD) and PTSD (PTSD/AUD). We examined residual symptoms of PTSD and AUD in 73 veterans with PTSD/AUD who completed a posttreatment assessment after being randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) or Seeking Safety (SS). We used logistic regression to identify differences (a) in residual PTSD and AUD symptoms among participants randomized to COPE versus SS and (b) among those with versus without a posttreatment PTSD/AUD diagnosis within both treatment conditions. Participants randomized to SS were more likely to report persistent avoidance, inability to experience positive emotions, hypervigilance, difficulty concentrating, and difficulty sleeping, ORs = 3.74–6.21. There were no differences between COPE and SS regarding the likelihood of persistent AUD symptoms. Participants without a posttreatment PTSD diagnosis had lower conditional probabilities of most symptoms, although exaggerated startle, OR = 0.71, and irritability/aggression, OR = 0.58, were most likely to persist. Participants without a posttreatment AUD diagnosis had lower conditional probabilities of most symptoms, although withdrawal, OR = 0.21; unsuccessful quit attempts, OR = 0.04; and higher intake, OR = 0.01, were most likely to persist. Findings indicate hyperarousal may warrant additional intervention following PTSD treatment. Residual AUD symptoms may relate to the enduring nature of some AUD symptoms rather than a lack of treatment efficacy.