Lee D. Katz

Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study.

UNLABELLED To quantitate hepatic glycogenolysis, liver glycogen concentration was measured with 13C nuclear magnetic resonance spectroscopy in seven type II diabetic and five control subjects during 23 h of fasting. Net hepatic glycogenolysis was calculated by multiplying the rate of glycogen breakdown by the liver volume, determined from magnetic resonance images. Gluconeogenesis was calculated by subtracting the rate of hepatic glycogenolysis from the whole body glucose production rate, measured using [6-3H]glucose. Liver glycogen concentration 4 h after a meal was lower in the diabetics than in the controls; 131 +/- 20 versus 282 +/- 60 mmol/liter liver (P < 0.05). Net hepatic glycogenolysis was decreased in the diabetics, 1.3 +/- 0.2 as compared to 2.8 +/- 0.7 mumol/(kg body wt x min) in the controls (P < 0.05). Whole body glucose production was increased in the diabetics as compared to the controls, 11.1 +/- 0.6 versus 8.9 +/- 0.5 mumol/(kg body wt x min) (P < 0.05). Gluconeogenesis was consequently increased in the diabetics, 9.8 +/- 0.7 as compared to 6.1 +/- 0.5 mumol/(kg body wt x min) in the controls (P < 0.01), and accounted for 88 +/- 2% of total glucose production as compared with 70 +/- 6% in the controls (P < 0.05). IN CONCLUSION increased gluconeogenesis is responsible for the increased whole body glucose production in type II diabetes mellitus after an overnight fast.

Reduced basal ganglia volumes in Tourette's syndrome using three‐dimensional reconstruction techniques from magnetic resonance images

Using a 1.5-tesla GE Signa MR scanner, we imaged the brains of 14 right-handed Tourettes syndrome (TS) patients (11 men, three women), aged 18 to 49 years, who had minimal lifetime neuroleptic exposure. We also studied an equal number of normal controls individually matched for age, sex, and handedness and group-matched for socioeconomic status. We circumscribed basal ganglia on sequential axial images from spin-echo proton density-weighted acquisitions (TR 1,700, TE 20; slice thickness, 3 mm with 1.5-mm skip) and submitted the images for three-dimensional processing at a computer graphics workstation. Our hypothesis of lenticular nucleus volume reduction in TS was confirmed for the left- but not the right-sided nucleus. Post hoc analyses revealed smaller mean volumes of the caudate, lenticular, and globus pallidus nuclei compared with controls on both the right and left. Further analyses of basal ganglia asymmetry indices suggest that TS basal ganglia do not have the volumetric asymmetry (left greater than right) seen in normal controls. These findings confirm and extend prior phenomenologic, neuropathologic, and neuroradiologic studies that implicate the basal ganglia in the pathogenesis of TS.

The disposal of an oral glucose load in patients with non-insulin-dependent diabetes.

Following glucose ingestion, tissue glucose uptake is enhanced and endogenous glucose production is inhibited, thus contributing to the maintenance of normal glucose tolerance. To examine whether these responses are disturbed in diabetes, glucose kinetics after oral glucose administration were studied in 12 non-insulin-dependent diabetic and 10 age- and weight-matched control subjects. A double tracer approach was used, whereby the endogenous glucose pool was labeled with 3-3H-glucose and the oral load with 1-14C-glucose. The two glucose tracers were separated in plasma by a two-step chromatographic procedure, and the two sets of isotopic data were analyzed according to a two-compartment model for the glucose system. Basally, glucose production was slightly higher in diabetics than in controls (2.51 +/- 0.24 v 2.28 +/- 0.11 mg/kg.min, NS) even though the former had higher plasma glucose (189 +/- 19 v 93 +/- 2 mg/dL, P less than .001) and insulin (23 +/- 4 v 12 +/- 1 microU/mL, P less than .05) concentrations. Following the ingestion of 1 g/kg of glucose, oral glucose appeared in the peripheral circulation in similar time-course and amount in the two groups (75 +/- 2% of the load over 3.5 hours in the diabetics v 76 +/- 3% in controls). Endogenous glucose production was promptly inhibited in diabetic and normal subjects alike, but the mean residual hepatic glucose production after glucose ingestion was significantly greater in the diabetic group (17 +/- 2 v 10 +/- 3 g/3.5 h, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Splanchnic and Peripheral Disposal of Oral Glucose in Man

Oral glucose (92 g) was administered to 22 healthy, young volunteers undergoing hepatic vein catheterization, and net splanchnic glucose output (SGO) was measured during the basal period and for 4 h after glucose ingestion. In the basal state, SGO averaged 1.90 ± 0.11 mg/min · kg. After glucose, SGO rose to a peak value of 6.65 ± 0.83 mg/min · kg at 30 min and returned to baseline by 3 h. Total SGO over 4 h was 69 ± 4 g; assuming complete absorption of the load, this amount represented 75% of the oral glucose. In a subgroup of six subjects, leg glucose uptake was simultaneously quantitated by femoral vein catheterization and leg blood flow measurement. In the postabsorptive state, glucose uptake by one leg was 24 ± 8 mg/min and increased to a mean value of 76 ± 7mg/min during the 4 h after glucose ingestion. Overall, 18 ± 2 g/4 h of glucose were taken up by one leg, which extrapolates to a total body muscle uptake of 65 ± 4 g over 4 h. We conclude that in normal man, well over 2/3 of an oral glucose load escapes splanchnic removal, and that the peripheral tissues quantitatively play the dominant role in glucose disposal.

13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus.

To determine the effect of insulin-dependent diabetes mellitus (IDDM) on rates and pathways of hepatic glycogen synthesis, as well as flux through hepatic pyruvate dehydrogenase, we used 13C-nuclear magnetic resonance spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units of hepatic glycogen, in combination with acetaminophen to sample the hepatic UDP-glucose pool and phenylacetate to sample the hepatic glutamine pool, during a hyperglycemic-hyperinsulinemic clamp using [1-13C]-glucose. Five subjects with poorly controlled IDDM and six age-weight-matched control subjects were clamped at a mean plasma glucose concentration of approximately 9 mM and mean plasma insulin concentrations approximately 400 pM for 5 h. Rates of hepatic glycogen synthesis were similar in both groups (approximately 0.43 +/- 0.09 mumol/ml liver min). However, flux through the indirect pathway of glycogen synthesis (3 carbon units-->-->glycogen) was increased by approximately 50% (P < 0.05), whereas the relative contribution of pyruvate oxidation to TCA cycle flux was decreased by approximately 30% (P < 0.05) in the IDDM subjects compared to the control subjects. These studies demonstrate that patients with poorly controlled insulin-dependent diabetes mellitus have augmented hepatic gluconeogenesis and relative decreased rates of hepatic pyruvate oxidation. These abnormalities are not immediately reversed by normalizing intraportal concentrations of glucose, insulin, and glucagon and may contribute to postprandial hyperglycemia.

In vivo glucose metabolism in the awake rat: Tracer and insulin clamp studies

The goals of this study were twofold: (1) to determine the in vivo dose-response relationship in the conscious, unstressed rat between the plasma insulin concentration and total body glucose uptake, and between plasma insulin and suppression of endogenous glucose production; and (2) to develop a physiologic compartmental model to describe the kinetics of plasma glucose in the rat in the basal state. In order to perform repeat insulin clamp studies in the same rat, chronic catheters were implanted in the aortic arch (via the carotid artery) and in the cardiac atrium (via the jugular vein), exteriorized, and fixed to the back of the skull with a dental cement cap. Insulin was infused at rates of 1.2, 2.4, 4.8, 12, and 24 mU/min.kg, and the plasma glucose was held constant at the basal level by a variable glucose infusion (euglycemic insulin clamp). The resulting steady-state plasma insulin concentrations ranged from 40 to 1,300 microU/mL. The dose-response curve for glucose uptake was sigmoidal in shape: in the basal state, total glucose utilization averaged 6.8 mg/min.kg at an insulin concentration of 9 microU/mL, half-maximal glucose uptake (18.3 mg/kg.min) occurred at a plasma insulin concentration between 70 and 80 microU/mL, and maximal uptake (36.6 mg/kg.min) was seen at an insulin level in excess of 100 microU/mL. Residual endogenous glucose production was evaluated by a prime-continuous infusion of (3-3H)-glucose. The dose-response curve for suppression of endogenous glucose output also was sigmoidal.(ABSTRACT TRUNCATED AT 250 WORDS)

Moderate-intensity aerobic training improves glucose tolerance in aging independent of abdominal adiposity.

OBJECTIVE: To test the hypothesis that training‐related improvements in glucose and insulin responses to an oral glucose tolerance test (OGTT) are independent of changes in abdominal adiposity.

Contribution of Hepatic Glycogenolysis to Glucose Production in Humans in Response to a Physiological Increase in Plasma Glucagon Concentration

The contribution of net hepatic glycogenolysis to overall glucose production during a physiological increment in the plasma glucagon concentration was measured in six healthy subjects (18–24 years, 68–105 kg) after an overnight fast. Glucagon (∼3 ng · kg−1 · min−1), somatostatin (0.1 μg · kg−1 · min−1), and insulin (0.9 pmol · kg−1 · min−1) were infused for 3 h. Liver glycogen concentration was measured at 15-min intervals during this period using 13C-labeled nuclear magnetic resonance spectroscopy, and liver volume was assessed from magnetic resonance images. The rate of net hepatic glycogenolysis was calculated from the decrease in liver glycogen concentration over time, multiplied by the liver volume. The rate of glucose appearance (Ra) was calculated from [3-3H]glucose turnover data using a two-compartment model of glucose kinetics. Plasma glucagon concentration rose from 136 ± 18 to 304 ± 57 ng/1 and plasma glucose concentration rose from 5.6 ± 0.1 to 10.4 ± 0.9 mmol/1 on initiation of the infusions. Mean baseline Ra was 11.8 ± 0.4 μmol · kg−1 · min−1, increased rapidly after the beginning of the infusions, reaching its highest value after 20–40 min, and returned to baseline by 140 min. Liver glycogen concentration decreased almost linearly (from 300 ± 19 mmol/1 liver at baseline to 192 ± 20 mmol/1 liver at t = 124 min) during 2 h after the beginning of the infusions, and the calculated mean rate of net hepatic glycogenolysis was 21.7 ± 3.6 μmol · kg−1 · min−1. Mean Ra during the same time period was 22.8 ± 2.3 μmol · kg−1 · min−1. Thus, net hepatic glycogenolysis accounted for 93 ± 9% of Ra. In conclusion, during the initial response to a physiological increment in plasma glucagon, 1) net hepatic glycogenolysis accounts for virtually all of the increase in hepatic glucose production, and 2) glucagons evanescent effect on hepatic glucose production is not caused by depletion of hepatic glycogen stores.

The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study.

Study Design. Randomized controlled trial comparing OP-1 (rhBMP-7) with iliac crest autograft in patients with symptomatic degenerative spondylolisthesis and spinal stenosis treated with decompression and uninstrumented posterolateral arthrodesis. Objective. To determine the safety and the clinical and radiographic efficacy of OP-1 (rhBMP-7) Putty as compared with an iliac crest bone autograft control in uninstrumented, single-level posterolateral spinal arthrodesis. Summary of Background Data. Preclinical and preliminary clinical data have demonstrated successful fusion and clinical outcomes with the use of OP-1 Putty in posterolateral spinal arthrodesis. No prior randomized controlled trial with adequate study power has been performed. Methods. A total of 335 patients were randomized in 2:1 fashion to receive either OP-1 Putty or autograft in the setting of an uninstrumented posterolateral arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis. Patients were observed serially with radiographs, clinical examinations, and appropriate clinical indicators, including ODI, Short-Form 36, and visual analog scale scores. Serum samples were examined at regular intervals to assess the presence of antibodies to OP-1. The primary end point, Overall Success, was analyzed at 24 months. The study was extended to include additional imaging data and long-term clinical follow-up at 36+ months. At the 36+ month time point, CT scans were obtained in addition to plain radiographs to evaluate the presence and location of new bone formation. Modified Overall Success, including improvements in ODI, absence of retreatment, neurologic success, absence of device-related serious adverse events, angulation and translation success, and new bone formation by CT scan (at 36+ months), was then calculated using the 24-month primary clinical endpoints, updated retreatment data, and CT imaging and radiographic end points. Results. OP-1 Putty was demonstrated to be statistically equivalent to autograft with respect to the primary end point of modified overall success. The use of OP-1 Putty when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. Although patients in the OP-1 Putty group demonstrated an early propensity for formation of anti-OP-1 antibodies, this resolved completely in all patients with no clinical sequelae. Conclusion. OP-1 Putty is a safe and effective alternative to autograft in the setting of uninstrumented posterolateral spinal arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis.

Human basal ganglia volume asymmetries on magnetic resonance images

The brains of 19 healthy adults, ages 18-49, were imaged on a GE Signa 1.5 T MR scanner. Basal ganglia were circumscribed on sequential axial proton density-weighted images (TR 1700, TE 20) and submitted for 3-dimensional reconstruction and volumetric analysis at a computer graphics workstation. The 15 right-handed patients (12 men, 3 women) had significantly larger left total basal ganglia volumes, which included larger globus pallidus and lenticular nuclei on the left, but larger caudate nuclei on the right. In contrast, basal ganglia asymmetries were not seen in four left-handers. No sex differences were detected. The basal ganglia appear to belong to an increasing number of CNS structures that display anatomical hemispheric lateralization.