Prolonged insulin resistance following insulin-induced hypoglycaemia

Summary Nineteen normal male volunteers underwent a 10-h glucose clamp study to examine the duration and mechanism of insulin resistance after hypoglycaemia. Dextrose delivery by the Biostator to maintain the target blood glucose level fell below baseline 2 h after induction of hypoglycaemia and remained suppressed for at least 7 h after insulin hypoglycaemia. Insulin secretion as manifested by C-peptide levels remained suppressed for 3–4 h after insulin hypoglycaemia despite return of blood glucose to baseline by 90 min. Glucose kinetic data (3-³H-glucose) performed in six of the subjects indicated that the prolonged insulin resistance was due to significantly increased hepatic glucose production and to suppressed glucose utilisation, persisting for at least 4 h after counterregulatory hormone levels had returned to normal. Post-hypoglycaemic insulin resistance as determined by dextrose delivery was markedly attenuated and the rise in hepatic glucose output totally eliminated in five hypopituitary subjects without growth hormone or cortisol responses to hypoglycaemia. We conclude that post-hypoglycaemic insulin resistance occurs in non-diabetic subjects and persists for at least 7 h following hypoglycaemia. This prolonged insulin resistance is largely related to release of growth hormone and cortisol.     

Prolonged survival in patients with hand-foot skin reaction secondary to cooperative sorafenib treatment

BACKGROUNDSorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation.AIMTo clarify the association between interventions for adverse events and patient prognosis.METHODSWe performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method.RESULTSWe enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman’s rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B.CONCLUSIONThe mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.     

Prolonged but partial impairment of the hypoglycaemic physiological response following short-term hypoglycaemia in normal subjects

Summary Recent studies have reported reduced endocrine and symptomatic responses to hypoglycaemia 18–24 h after antecedent hypoglycaemia in both non-diabetic subjects and those with insulin-dependent diabetes mellitus. We examined these and peripheral physiological responses in eight nondiabetic subjects aged 23–35 years in the week following antecedent hypoglycaemia. Blood glucose levels were held at plateaus of 5 mmol/l and 2.5 mmol/l for 30 min during hyperinsulinaemic (60 mU · m^–2 · min^–1) morning clamps on days 1, 3 and 8 of two study periods separated by at least 4 weeks. Measurements were made at time 0, 15 and 30 min of each plateau on each day. On the afternoon of Day 1 we also induced either euglycaemia with a blood glucose level of 5 mmol/l (control week) or hypoglycaemia of 2.9 mmol/l (hypo week) for 2 h in random order. The adrenaline response to morning hypoglycaemia (p<0.01 on all days) was attenuated on Day 3 (p<0.05) and Day 8 (p<0.05) compared to Day 1 of hypo week only. Sweating was also attenuated on Day 3 (p<0.05) and Day 8 (p<0.02) of hypo week only. Noradrenaline levels and tremor increased during hypoglycaemia on each study day (p<0.05) but did not differ between days in either week. During hypo week only, the total symptom score response to hypoglycaemia was attenuated on Day 3 (p<0.03) but not Day 8 (p=0.10). Autonomic symptoms were similarly affected. In summary, the physiological responses to hypoglycaemia are affected differentially by antecedent hypoglycaemia with sweating and adrenaline responses remaining impaired for at least 5 days.Abbreviations RMS Root mean square - RIA radioimmunoassay - AUC area under curve - IDDM insulin dependent diabetes mellitus - hypo hypoglycaemia     

Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes

Aims/hypothesis It has been postulated that hypoglycaemia-related cardiac dysrhythmia and, in particular, prolonged cardiac repolarisation, may contribute to increased mortality rates in children and adolescents with type 1 diabetes.Methods We examined the prevalence of prolonged QT interval on ECG during spontaneous hypoglycaemia in 44 type 1 diabetic subjects (aged 7–18 years), and explored the relationships between serial overnight measurements of QT interval corrected for heart rate (QTc) and serum glucose, potassium and epinephrine levels. Each subject underwent two overnight profiles; blood was sampled every 15 min for glucose measurements and hourly for potassium and epinephrine. Serial ECGs recorded half-hourly between 23.00 and 07.00 hours were available on 74 nights: 29 with spontaneous hypoglycaemia (defined as blood glucose <3.5 mmol/l) and 45 without hypoglycaemia.Results Mean overnight QTc was longer in females than in males (412 vs 400 ms, p=0.02), but was not related to age, diabetes duration or HbA₁c. Prolonged QTc (>440 ms) occurred on 20 out of 74 (27%) nights, with no significant differences between male and female subjects, and was more prevalent on nights with hypoglycaemia (13/29, 44%) than on nights without (7/45, 15%, p=0.0008). Potassium levels were lower on nights when hypoglycaemia occurred (minimum potassium 3.4 vs 3.7 mmol/l, p=0.0003) and were inversely correlated with maximum QTc (r=–0.40, p=0.03). In contrast, epinephrine levels were not higher on nights with hypoglycaemia and were not related to QTc.Conclusions/interpretation In young type 1 diabetic subjects, prolonged QTc occurred frequently with spontaneous overnight hypoglycaemia and may be related to insulin-induced hypokalaemia.     

Prolonged electrical systole and QT greater than QS2 secondary to coronary artery disease

Dyssynchronous depolarization-repolarization in the left ventricular (LV) myocardium may produce QT greater than QS2 or long QT. In 41 patients with coronary artery disease (CAD) and LV aneurysm, 46 patients with CAD and a history of acute myocardial infarction (AMI) but no LV aneurysm, and 52 patients with CAD without previous AMI, QT and QS2 were measured simultaneously at a speed of 100 mm/s within 48 hours of cardiac catheterization. Patients receiving class I antiarrhythmic drugs were excluded. The incidence of QT greater than QS2 was significantly greater in patients with LV aneurysm (71%) than in those with previous AMI (22%) and those with CAD but no previous AMI (20%) (p less than 0.001). Likewise, the incidence of long QT corrected for heart rate was significantly greater in patients with LV aneurysm (54%) than in those with previous AMI (7%) and those with CAD and no previous AMI (6%) (p less than 0.0001). The incidence of QT greater than QS2 in another 19 patients with previous AMI who were receiving digitalis therapy was significantly greater (65%) than in those with previous AMI but not receiving digitalis therapy (22%) (p less than 0.001). The incidence of long QT corrected for heart rate and QT greater than QS2 was not statistically different between patients with previous AMI and those with CAD but no previous AMI. The QT greater than QS2 or long QT in patients with aneurysm is probably a result of dyssynchronous depolarization or repolarization within or in the border zone of the LV aneurysm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolonged remission of Epstein-Barr virus associated lymphoma secondary to T cell-depleted bone marrow transplantation

High grade non-Hodgkin's lymphoma developed 42 days after allogeneic T cell-depleted bone marrow transplantation (BMT) for idiopathic aplastic anaemia. DNA hybridization studies confirmed clonality and incorporation of Epstein-Barr virus (EBV) genome. Prolonged remission followed low dose chemotherapy, local radiotherapy and early withdrawal of cyclosporin.     

Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia

This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.     

Sleep and the response to hypoglycaemia

Undetected nocturnal hypoglycaemia frequently occurs in patients with diabetes, having a negative influence on well-being, counterregulation against and awareness of subsequent hypoglycaemia, and even causing sudden death in some cases most likely by inducing cardiac arrhythmia. Sleep markedly weakens the neuroendocrine defence mechanism against hypoglycaemia by shifting the glycaemic threshold for counterregulatory activation to lower levels. While hypoglycaemia triggers awakening in healthy subjects, patients with type 1 diabetes frequently fail to awake in the presence of low plasma glucose levels. Little is known about the frequency of and responses to nocturnal hypoglycaemia in patients with type 2 diabetes. Unfortunately, effective strategies to prevent or even safely detect nocturnal hypoglycaemia are still lacking. Taken together, hypoglycaemia occurring during sleep presents a major, often neglected problem in the management of diabetic patients. Different aspects of this phenomenon such as responses to and consequences of nocturnal hypoglycaemia as well as strategies for its prevention are highlighted in this review.     

Antecedent hypoglycaemia attenuates vascular endothelial growth factor response to subsequent hypoglycaemia in healthy men

Aim The plasma concentration of vascular endothelial growth factor (VEGF) has recently been shown to increase sharply in response to hypoglycaemia and, thus, has been proposed as having a role in hypoglycaemia counter‐regulation. Many counter‐regulatory hormones show a reduced response after antecedent hypoglycaemia. We therefore investigated whether this decrease in responsiveness with repetitive hypoglycaemia also pertains to VEGF. Methods Three hypoglycaemic clamp experiments were performed on two consecutive days in 15 healthy men. VEGF response was assessed during the first and last hypoglycaemic period. Results As expected, plasma VEGF concentrations rose markedly during the clamps (P < 0.001). The increase was distinctly blunted during the third (+13 ± 8 pg/ml) as compared with the first (+54 ± 18 pg/ml) hypoglycaemic clamp (P = 0.046). Conclusion This data confirms that circulating VEGF concentrations increase acutely during hypoglycaemia. Like the counter‐regulatory hormones, the hypoglycaemia‐induced rise in VEGF is attenuated after antecedent hypoglycaemia. The origin of increased systemic VEGF concentration during hypoglycaemia and its physiological role remains to be defined.     

Gender differences in counterregulation to hypoglycaemia

Summary To investigate the effect of gender on catecholamine responses to hypoglycaemia, single-step euglycaemic-hypoglycaemic clamps have been performed in 14 healthy men and 17 women. Adrenaline responses were 44% lower in females (p<0.01) and noradrenaline 17% lower (p=0.08). In response to low-dose intravenous insulin infusion (0.3 mU · kg^–1 · min^–1), plasma glucose fall and counter-regulation in seven men and seven women had a different course (p<0.001), with different glucose kinetics. In men, endogenous glucose output recovered quickly to levels that exceeded basal; in women suppression of endogenous glucose output was more prolonged, without rates ever exceeding basal (p<0.05). Peripheral glucose uptake was stimulated in men only. The hormones of acute glucose counter-regulation (catecholamines and glucagon) did not differ between the sexes during this challenge, the catecholamine response in the women being supported by the continuous fall in plasma glucose. These results suggest that: 1) catecholamine responses to moderately controlled hypoglycaemia are diminished in women, and 2) Peripheral insulin sensitivity in men is enhanced over that of women but hepatic sensitivity to insulin may be greater in women.     

Prolonged recirculation is required to detect secondary metabolic and hemodynamic deterioration after superior mesenteric artery occlusion

We evaluated late (4 hrs) effects of reperfusion on hemodynamics after 30 or 60 min occlusion of the superior mesenteric artery (SMA) in a rat model. Spontaneously breathing animals (n=30) underwent occlusion of the SMA for 0 (sham), 30 (SMAO_30) or 60 min (SMAO_60) followed by reperfusion with normal saline. Abdominal blood flow (ABF), SMA blood flow (SBF), arterial blood pressure and heart rate were recorded continuously. Systemic vascular resistance (SVR) and SMA vascular resistance (MVR) were calculated at baseline and after 240 min reperfusion (240R). All animals survived in SMAO_30 and sham, two died in SMAO_60 after 120R. ABF remained constant in all groups. SVR increased in SMAO_30 and sham and decreased in SMAO_60 at 240R. SBF was significantly lower after reperfusion in ischemia groups as compared to sham. After 120R, SBF had increased significantly in SMAO_60 versus SMAO_30. MVR increased significantly in SMAO_30 but not in SMAO_60 and sham at 240R. 60 minutes SMA occlusion revealed early hemodynamic changes of septic circulation with increased blood flow in the SMA, decreased SVR, and pseudo-normalization of MVR. Prolonged observation periods are required to detect these significant changes which are overlooked when only studying 120 minutes of reperfusion as usually done.     

Comparison of alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction,no hypoglycaemia and no weight gain in type 2 diabetes mellitus

This was a post hoc analysis of a 2‐year, double‐blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.