Subnormal response of plasma glucose concentration to glucagon despite adequate glycogenolysis: the importance of kinetic measurements

The plasma glucose concentration response to a glucagon bolus is considered an important diagnostic tool in hypoglycemia of unknown origin. The response of plasma glucose concentration to glucagon can however also be misleading in the differential diagnosis. In a 3-week-old male infant suffering recurrent severe preprandial hypoglycemia and dependent on continuous i.v. glucose infusion, extensive diagnostic screening including a liver biopsy did not lead to a diagnosis. Based on an insufficient glycemic response (twice) to a glucagon bolus, a disorder of glycogenolysis was suspected. Glucose production and gluconeogenesis were measured (glycogenolysis calculated) during diminishing i.v. glucose infusion and after a glucagon bolus. Reducing glucose infusion resulted in a steep increase in glycogenolysis and gluconeogenesis, maintaining total glucose turnover (production plus infusion) constant at ±9 mg · kg⁻¹ · min⁻¹ (±60% gluconeogenesis, ±40% glycogenolysis). Plasma glucose concentration however decreased from 4.9 mmol/l to 3.4 mmol/l. Glucagon increased glucose production by 50% but resulted in only a minor increase in glucose concentration. Conclusion As glucose concentration depends on the balance between glucose production and utilization (uptake), facilitated glucose uptake rather than impaired glycogenolysis explains the hypoglycemic episodes in this patient. A subnormal response of plasma glucose to glucagon therefore does not necessarily imply a disturbance in glycogenolysis. In cases of hypoglycemia of unknown origin, measurement of glucose kinetics with stable isotopes is indicated. Received: 12 January 2000 and in revised form 11 June 2000 and 13 August 2000 / Accepted: 7 September 2000     

Dynamic sagittal alignment and compensation strategies in adult spinal deformity during walking

BACKGROUND CONTEXTRadiographic evaluation in adult spinal deformity (ASD) offers no information on spinopelvic alignment and compensation during dynamic conditions. Motion analysis offers the potential to bridge the gap between static radiographic and dynamic alignment measurement, increasing our understanding on how ASD impacts function.PURPOSEThis study aimed to explore the changes in sagittal alignment and compensation strategies in ASD between upright standing and walking, compared to control subjects and within different sagittal alignment groups. Ten patients were measured pre- and six months postoperatively to explore the impact of surgical alignment correction on gait.STUDY DESIGNProspective study.SAMPLE SIZEFull protocol: 58 ASD and 20 controls; Spinal kinematic analysis: 43 ASD and 18 controls; Postoperative analysis: 10 ASD.OUTCOME MEASURESStanding and walking sagittal spinopelvic (thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvis), and lower limb kinematics, spinopelvic changes between standing and walking (? ie, difference between mean dynamic and static angle), lower limb kinetics, spatiotemporal parameters, balance (BESTest), patient-reported outcome scores (SRS-22r, ODI, and FES-I) and radiographic parameters.METHODSMotion analysis was used to assess the standing and walking spinopelvic and lower limb kinematics, as well as the lower limb kinetics during walking. All parameters were compared between controls and patients with ASD, divided in three groups based on their sagittal alignment (ASD 1: decompensated sagittal malalignment; ASD 2: compensated sagittal malalignment; ASD 3: scoliosis and normal sagittal alignment). Ten patients were reassessed 6 months after spinal corrective surgery. Continuous kinematic and kinetic data were analyzed through statistical parametric mapping.RESULTSAll patient groups walked with increased forward trunk tilt (?SVA=41.43 mm, p<.001) in combination with anterior pelvic tilt (?Pelvis=2.58°, p<.001) compared to standing, as was also observed in controls (?SVA=37.86 mm, p<.001; ?Pelvis=1.62°, p=.012). Patients walked with increased SVA, in combination with decreased LL and alterations in lower limb kinematics during terminal stance and initial swing, as well as altered spatiotemporal parameters. Subgroup analysis could link these alterations in gait to sagittal spinopelvic malalignment (ASD 1 and 2). After surgical correction, lower limb kinematics and spatiotemporal parameters during gait were not significantly improved.CONCLUSIONSTo compensate for increased trunk tilt and pelvic anteversion during walking, patients with sagittal malalignment show altered lower limb gait patterns, which have previously been associated with increased risk of falling and secondary lower limb pathology. Since surgical correction of the deformity did not lead to gait improvements, further research on the underlying mechanisms is necessary to improve our understanding of how ASD impacts function.     

The relation between postprandial glucagon-like peptide-1 release and insulin sensitivity before and after bariatric surgery in humans with class II/III obesity

BackgroundGlucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for the human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB).ObjectivesTo elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB.SettingClinical research facility in a university hospital.MethodsWe recruited 35 patients scheduled for RYGB and assessed their plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a 2-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Out of 35 subjects, 10 were studied both before surgery and at 1 year of follow-up.ResultsPlasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index. At 1 year after RYGB, participants had lost 24% ± 6% of their body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted.ConclusionsPostprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and 1 year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.     

Cognitive Outcome After Deep Brain Stimulation for Refractory Obsessive–Compulsive Disorder: A Systematic Review

IntroductionDeep brain stimulation (DBS) is an effective treatment for refractory obsessive–compulsive disorder (OCD). Neuropsychological assessment contributes to DBS treatment in several ways: it monitors the cognitive safety of the treatment, identifies beneficial or detrimental cognitive side effects, and it could aid to explain variability in treatment outcome, and possibly the treatment's working mechanism(s).BackgroundThis systematic review assessed the cognitive safety of DBS for OCD and explored whether changes in cognitive function may help explain its working mechanism(s).Materials and MethodsEMBASE, PubMed/Medline, Psycinfo, and the Cochrane Library were systematically searched for studies reporting cognitive outcomes following DBS for OCD. Searches were completed in November 2020. Included studies were appraised for study design and quality according to National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools.ResultsFive randomized controlled trials and ten observational studies comprising a total of 178 patients were analyzed collectively. Variable outcomes of DBS were observed in the domains of attention, memory, executive functioning, and in particular, cognitive flexibility.ConclusionAlthough individual studies generally do not report cognitive deterioration after DBS for OCD, the variability of study designs and the multitude of cognitive measures used precluded a meta-analysis to confirm its safety and recognition of a cognitive pattern through which the efficacy of DBS for OCD might be explained. In the future, prospective studies should preferably include a standardized neuropsychological assessment battery specifically addressing executive functioning and have a longer-term follow-up in order to demonstrate the cognitive safety of the procedure. Such prospective and more uniform data collection may also contribute to our understanding of the working mechanisms of DBS in OCD.     

Pre-operative nutritional status does not alter the metabolic response to major gastrointestinal surgery in patients with oesophageal cancer

Malnutrition is associated with an increased incidence of perioperative morbidity and mortality. To evaluate the effect of malnutrition on the metabolic and inflammatory response to surgery in patients with oesophageal cancer, we studied the effects of oesophagectomy in six patients with major (13.9 (se 1.3) %) weight loss and five patients with minor (0.7 (se 0.6) %) weight loss in the 6 months before to surgery. Rates of appearance (Ra) of glucose, glycerol, leucine and urea were determined by stable isotopically labelled tracer infusion before and after surgery. C-reactive protein was measured as an inflammation marker. BMI was lower in the patients with major weight loss than those with minor weight loss (20.3 (se 0.7) and 24.9 (se 1.5) kg/m2, P = 0.02). With the exception of greater glucose Ra in the major weight loss than minor weight loss subjects (11.1 (se 0.3) v. 9.5 (se 0.3) mumol/kg per min, P = 0.01), there were no differences in substrate kinetics before surgery between groups. Surgery increased glucose Ra, leucine Ra and urea Ra by 41, 24 and 58 %, respectively, in the total group. Changes in substrate kinetics in response to surgery were not different between patients with major and minor weight loss. Surgery increased C-reactive protein concentrations to a comparable extent in both groups. In conclusion, major upper gastrointestinal tract surgery in patients with oesophageal cancer elicits a catabolic response, characterized by increased inflammation, glucose production and protein breakdown. However, this catabolic response does not seem to be influenced by pre-operative nutritional status.     

Hepatic insulin resistance in antipsychotic naive schizophrenic patients: stable isotope studies of glucose metabolism

OBJECTIVE: Our objective was to measure insulin sensitivity and body composition in antipsychotic-naive patients with DSM IV schizophrenia and/or schizoaffective disorder compared with matched controls. DESIGN: Seven antipsychotic medication-naive patients fulfilling the DSM IV A criteria for schizophrenia/schizoaffective disorder were matched for body mass index, age, and sex with seven control subjects. We measured endogenous glucose production and peripheral glucose disposal using a hyperinsulinemic euglycemic clamp (plasma insulin concentration approximately 200 pmol/liter) in combination with stable isotopes. Fat content and fat distribution were determined with a standardized single-slice computed tomography scan and whole body dual-energy x-ray absorptiometry. RESULTS: Endogenous glucose production during the clamp was 6.7 micromol/kg x min (sd 2.7) in patients vs. 4.1 micromol/kg x min (sd 1.6) in controls (P = 0.02) (95% confidence interval -5.2 to 0.006). Insulin-mediated peripheral glucose uptake was not different between patients and controls. The amount of sc abdominal fat in patients was 104.6 +/- 28.6 cm(3) and 63.7 +/- 28.0 cm(3) in controls (P = 0.04) (95% confidence interval 4.4-77.2). Intraabdominal fat and total fat mass were not significantly different. CONCLUSIONS: Antipsychotic medication-naive patients with schizophrenia or schizoaffective disorder display hepatic insulin resistance compared with matched controls. This finding cannot be attributed to differences in intraabdominal fat mass or other known factors associated with hepatic insulin resistance and suggests a direct link between schizophrenia and hepatic insulin resistance.     

Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand

In order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-(2)H(2)] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5-3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: -31.9% vs. -17.9% (p = 0.007), GGL: -66.2% vs. -50.8% (p = 0.465) and GNG 6.8% vs. 19.5% (p = 0.465). Plasma alanine levels were significantly lower (p = 0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in children.     

Adaptation of glucose production and gluconeogenesis to diminishing glucose infusion in preterm infants at varying gestational ages

In preterm infants low plasma glucose concentrations are frequently observed. We hypothesized that the infants' ability to adapt endogenous glucose production to diminishing exogenous supply is disturbed, but will improve with increasing gestational age. Glucose production rate and gluconeogenesis were measured using stable isotope techniques with [6,6-2H2]glucose and [2-13C]glycerol in 19 preterm infants (10 < or = 30 wk and nine >30 wk gestational age) on d 5.0 +/- 1.4 of life. Exogenous glucose was administered at a rate of 33 micromol x kg-1 x min-1 followed by 22 micromol x kg-1 x min-1. In the first 2 h after the decrease in exogenous supply, plasma glucose concentration declined comparably in both groups: < or =30 wk, from 4.3 +/- 1.2 to 3.2 +/- 0.9 mM; >30 wk, from 3.7 +/- 0.7 to 3.0 +/- 0.6 mM. Thereafter, only in infants >30 wk an increase was observed, to 3.4 +/- 0.8 mM. Glucose production rate increased comparably in both groups: < or =30 wk, from 6.0 +/- 4.1 to 8.8 +/- 3.4 micromol x kg-1 x min-1; >30 wk, from 7.8 +/- 4.6 to 11.6 +/- 5.2 micromol x kg-1 x min-1. This increase was equivalent to approximately 30% of the decline in exogenous glucose. Gluconeogenesis increased comparably in both groups: <30 wk, from 3.2 +/- 1.2 to 4.5 +/- 1.3 micromol x kg-1 x min-1; >30 wk, from 4.3 +/- 1.9 to 6.8 +/- 2.9 micromol x kg-1 x min-1. We conclude that preterm infants can only partly compensate a decline in exogenous glucose supply by increasing endogenous glucose production rate, probably because of limitations in the final common pathway of intracellular glucose metabolism (i.e. glucose-6-phosphatase). The ability to maintain the plasma glucose concentration after a decrease in exogenous supply is better preserved in infants >30 wk owing to more efficient adaptation of peripheral glucose utilization.