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S Kalhan

Publications and source records attributed to S Kalhan.

At least 19 recordsLinked to original sources
PubMed2001

Euglycemic clamp study in clozapine-induced diabetic ketoacidosis.

OBJECTIVE: To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. CASE SUMMARY: A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. DISCUSSION: Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale. CONCLUSIONS: The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.

Adult↗
PubMed2000

Gluconeogenesis in the fetus and neonate.

Gluconeogenesis (GNG), a key metabolic process, involves the formation of glucose and glycogen from non-glucose precursors via pyruvate. In the strict sense, it also includes the contribution of glycerol as well as recycled glucose carbon (Cori's cycle). The developmental expression of GNG in the fetus and newborn and the quantitative contribution of GNG to glucose has been extensively investigated in humans and other mammalian species. Data from studies in rodents, rabbits, and sheep fetuses show that the development of GNG is a well-orchestrated process that is regulated by the expression of specific factors involved in the transcription of the genes for specific regulating enzymes, which catalyze GNG. These transcription factors and the genes for gluconeogenic enzymes are expressed at specific time periods during development. Although the fetus has the potential for GNG, the actual formation of glucose from pyruvate is not apparent until after birth because the rate limiting enzyme phosphoenolpyruvate carboxykinase appears only after birth in the immediate newborn period. Several tracer isotope methods have been employed to quantify the contribution of GNG to glucose. Of these, the recently developed stable isotope techniques with deuterium labeled water and the mass isotopomer distribution analysis appear to be the most precise and easily applicable in human studies. The available data show that in the human newborn, GNG appears soon after birth and contributes 30% to 70% to glucose produced. Application of new molecular biology techniques, in combination with sensitive tracer isotopic methods, will allow us to identify and examine metabolic disorders that impact GNG and help develop intervention strategies.

Animals↗
PubMed2000

Hypoglycemia: what is it for the neonate?

The definition of hypoglycemia in the newborn infant has remained controversial because of lack of significant correlation between plasma glucose concentration, clinical symptoms, and long-term sequelae. A threshold value for plasma glucose at which clinical intervention should be considered is important because of the potential for serious neurological injury. In this review, we have described threshold values for plasma glucose in the newborn infant, based upon available data, at which the clinician should consider close monitoring and therapeutic interventions aimed at increasing the glucose level. In clinically symptomatic infants, plasma glucose concentrations of 45 mg/dL (2.5 mmol/L) or less should be considered as threshold for intervention. In an asymptomatic baby and in those at risk for hypoglycemia, irrespective of gestational and postnatal age, plasma glucose values less than 36 mg/dL (2.0 mmol/L) should be considered as threshold levels. Variances from these criteria, as in breast-fed infants, are discussed. The threshold values described for surveillance and intervention should be separated from the targeted therapeutic values which should be in the range of 72-90 mg/dL (4-5 mmol/L).

Age Factors↗
PubMed2000

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Journal Article↗
PubMed1998

Quantification of gluconeogenesis in cirrhosis: response to glucagon.

BACKGROUND & AIMS: Accelerated starvation and early recruitment of alternate fuels in cirrhosis have been attributed to reduced availability of hepatic glycogen. The aim of this study was to measure gluconeogenesis (as a marker of protein oxidation) in relation to total glucose production and glucagon-stimulated glycogenolysis. METHODS: Glucose and urea production, gluconeogenesis, and glycogenolysis were calculated using stable isotope methods before and during glucagon infusion (3 ng. kg-1. min-1) in 5 cirrhotic patients and 5 matched controls before and after glycogen repletion. RESULTS: In the basal state, cirrhotic patients had a normal rate of glucose production, but the contribution of gluconeogenesis was increased (74.3% +/- 4.1% vs. 55. 6% +/- 12.1%; P < 0.005). Glycogen repletion normalized the rate of gluconeogenesis. The glycemic response to glucagon (3 ng. kg-1. min-1) was blunted in cirrhotic patients because of a lower rate of glycogenolysis (0.63 +/- 0.23 vs. 1.22 +/- 0.23 mg. kg-1. min-1; P < 0.01) and was not affected by glycogen repletion. Despite increased gluconeogenesis, the simultaneously measured rate of urea synthesis was lower in cirrhotic patients (3.11 +/- 1.02 vs. 5.0 +/- 1.0 mg/kg; P < 0.05). CONCLUSIONS: These data show that in cirrhosis, glucose production is sustained by an increased rate of gluconeogenesis. The hepatic resistance to glucagon action is not caused by reduced glycogen stores.

Adult↗
PubMed1997

Glucose turnover and gluconeogenesis in human pregnancy.

The rate of appearance (Ra) of glucose in plasma and the contribution of gluconeogenesis were quantified in normal pregnant women early ( approximately 10 wk) and late ( approximately 34 wk) in gestation. Their data were compared with those of normal nonpregnant women. Glucose Ra was measured using the [U-13C]glucose tracer dilution method. Gluconeogenesis was quantified by the appearance of 2H on carbon 5 and 6 of glucose after deuterium labeling of body water pool. Weight-specific glucose Ra was unchanged during pregnancy (nonpregnant, 1.89+/-0.24; first trimester, 2.05+/-0.21; and third trimester 2.17+/-0.28 mg/kg.min, mean+/-SD), while total glucose Ra was significantly increased (early, 133.5+/-7.2; late, 162.6+/-16.4 mg/min; P = 0.005). The fractional contribution of gluconeogenesis via pyruvate measured by 2H enrichment on C-6 of glucose (45-61%), and of total gluconeogenesis quantified from 2H enrichment on C-5 of glucose (i.e. , including glycerol [68-85%]) was not significantly different between pregnant and nonpregnant women. Inasmuch as total glucose Ra was significantly increased, total gluconeogenesis was also increased in pregnancy (early pregnancy, 94.7+/-15.9 mg/min; late pregnancy, 122.7+/-9.3 mg/min; P = 0.003). These data demonstrate the ability of the mother to adapt to the increasing fetal demands for glucose with advancing gestation. The mechanism for this unique quantitative adjustment to the fetal demands remains undefined.

3-Hydroxybutyric Acid↗
PubMed1996

Glucose and lactate kinetics during a short exercise bout in pregnancy.

Pregnancy is considered diabetogenic. Although exercise has been advocated to assist in metabolic control of the nonpregnant diabetic individual, there is a paucity of data about the metabolic effects of exercise during pregnancy. To examine whether moderate exertion may be beneficial in the maintenance of maternal carbohydrate homeostasis, glucose and lactate kinetics were measured in the third trimester in five pregnant nondiabetic women (gestational age, 34.2 +/- 0.1 weeks [mean +/- SE]) by infusion of 45 microg x kg(-1) x min(-1) [6,6-2H2]glucose and 70 microg x kg(-1) x min(-1) [U-13C]lactate tracers. Subjects were observed at rest for determination of baseline steady-state kinetics over a 30-minute period, and then they exercised for 30 minutes at 60% maximum oxygen consumption (VO2max) and were evaluated for 30 minutes postexercise. Glucose and lactate kinetics and lactate oxidation were measured throughout the exercise protocol. This study was repeated postpartum in all individuals at least 6 weeks after delivery. Compared with the steady-state preinfusion period, plasma glucose concentration was not elevated during exercise in either group, nor was plasma lactate concentration significantly different in either group. Glucose kinetics did not change during exercise, but lactate kinetics increased in both groups. V02 and percent of lactate C contribution to CO2, an indication of lactate oxidation, increased proportionally in both groups during exercise. Metabolic perturbations, as measured by glucose and lactate kinetics, do not appear to be different during the third trimester of pregnancy during a relatively short bout of exercise compared with the nonpregnant state.

Adult↗
PubMed1993

Glucose metabolism during fasting through human pregnancy: comparison of tracer method with respiratory calorimetry.

Glucose turnover and glucose oxidation were quantified in six normal pregnant women serially throughout pregnancy, using [U-13C]glucose tracer in combination with open-circuit indirect respiratory calorimetry. Five normal nonpregnant women were studied for comparison. With advancing gestation and increase in maternal body weight, there was a proportionate increase in the rate of appearance (Ra) of glucose so that Ra expressed per kilogram body weight did not change from the first to third trimester. The tracer measured rate of glucose oxidation expressed per kilogram body weight also did not change significantly throughout pregnancy. Oxygen consumption (VO2) in pregnant subjects did not differ from that in nonpregnant subjects. However, the respiratory exchange ratio (RER) increased significantly during pregnancy (0.88 +/- 0.53 3rd trimester and 0.76 +/- 0.50 nonpregnant, P < 0.01). The estimated contribution of carbohydrate to VO2 measured by respiratory calorimetry was greater than that measured by the tracer method. This discrepancy became wider as the respiratory quotient increased in late pregnancy. These data suggest that maternal glucose metabolism adjusts throughout pregnancy to meet the increased demands of the conceptus. The discrepancy between tracer method and respiratory calorimetry was probably due to the contribution of (fetal) lipogenesis and (maternal) gluconeogenesis to RER.

Adult↗
PubMed1992

Glucose kinetics following administration of an intravenous fat emulsion to low-birth-weight neonates.

To evaluate the mechanism(s) of the observed increase in plasma glucose concentration following the administration of an intravenous fat emulsion to the neonate, we measured glucose kinetics in eight low-birth-weight neonates by the prime constant rate infusion technique with D-[6,6-2H2]glucose at a rate of 0.22 +/- 0.01 mumol.kg-1 x min-1 (39.4 +/- 1.3 micrograms.kg-1 x min-1) while the neonates received 32 +/- 5 mumol.kg-1 x min-1 glucose (6.3 +/- 1.1 mg.kg-1 x min-1) plus an amino acid mixture (parenteral alimentation) alone and in combination with an intravenous fat emulsion (Intralipid). Following the latter combination, there were significant increases in plasma glucose concentration [4.07 +/- 0.11 (73 +/- 2 mg/dl) to 5.00 +/- 0.22 mmol/l (90 +/- 4 mg/dl); P < 0.01] and in plasma insulin concentration [72 +/- 14 (10 +/- 2 microU/ml) to 172 +/- 36 pmol/l (24 +/- 5 microU/ml); P < 0.05]. The parenteral alimentation and intravenous fat effusion combination did not affect the glucose production rate: 0.15 +/- 0.05 mumol.kg-1 x min-1 (0.03 +/- 0.01 mg.kg-1 x min-1) during the parenteral alimentation alone and 0.16 +/- 0.05 mumol.kg-1 x min-1 (0.03 +/- 0.01 mg.kg-1 x min-1) when parenteral alimentation was combined with an intravenous fat emulsion. We conclude that the increased plasma glucose concentration seen in association with administration of parenteral alimentation combined with an intravenous fat emulsion to the premature neonate is not due to enhanced glucose production but could be the result of alterations in glucose utilization.

Blood Glucose↗
PubMed1992

Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: effect of maternal diabetes and intrauterine growth retardation.

Kinetics of glycerol metabolism and triglyceride/fatty acid cycling were quantified in 12 healthy, normal, appropriate-for-gestational-age (AGA) infants, eight small-for-gestational-age (SGA) infants, and five infants of insulin-dependent diabetic mothers (IDM) at less than 48 h of age. Stable isotope-labeled [2-13C]glycerol and [6,6-2H2]glucose in combination with indirect respiratory calorimetry were used. The tracers were used as constant rate infusion and steady state isotopic enrichment of glucose, glycerol, and bicarbonate was measured by mass spectrometric methods. After a 7- to 9-h fast, the plasma glucose, glycerol, and FFA concentrations were similar in the AGA and IDM groups. In the SGA group, the plasma glucose concentration was significantly lower than that in the AGA group throughout the study, but plasma FFA and glycerol concentrations were not different from those in the AGA infants. Plasma betahydroxybutyrate concentration was significantly elevated in the AGA group compared with IDM and SGA infants (AGA 0.59 +/- 0.39, SGA 0.35 +/- 0.09, IDM 0.33 +/- 0.21 mmol/L; mean +/- SD). The rate of appearance of glycerol was significantly elevated (p less than 0.05) in SGA infants (AGA 9.47 +/- 2.11, IDM 9.55 +/- 2.14, SGA 12.15 +/- 3.87 mumol/kg.min). Between 80 and 90% of glycerol turnover was converted to glucose, accounting for 20% of glucose turnover with no significant difference in the three groups. Approximately 35% of glycerol carbon was recovered in the bicarbonate (CO2) pool. Less than 5% of CO2 carbon was derived from glycerol. Estimation of triglyceride-fatty acid cycle revealed that the triglyceride energy mobilized was increased in SGA infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1992

Effects of growth hormone releasing hormone on insulin action and insulin secretion in a hypopituitary patient evaluated by the clamp technique.

The effect of growth hormone releasing hormone (GHRH-44) therapy on insulin action and secretion was evaluated in a hypopituitary patient after one month and one year of treatment. Hepatic and peripheral insulin action was studied with the hyperinsulinemic-euglycemic clamp in combination with [6,6-2H2]glucose tracer infusion. First and second phase insulin secretion was assessed with the hyperglycemic clamp. Prior to GHRH-44 therapy the hypopituitary patient had higher insulin mediated glucose disposal rate and lower basal and stimulated insulin concentrations by more than two standard deviations from the mean of a control group. Following therapy there was no change in basal hepatic glucose production; however, there was evidence of diminished peripheral insulin action. This was manifested by decreased insulin mediated glucose disposal during the hyperinsulinemic-euglycemic clamp, and increased insulin secretion during the hyperglycemic clamp. We conclude that GHRH-44 therapy in this patient was associated with decreased peripheral insulin action which was compensated for by increased insulin secretion.

Child↗
PubMed1991

Indium 111 oxine-labeled leukocytes for early diagnosis of ischemic enterocolitis.

The feasibility of the use of indium 111 oxine-labeled autologous leukocytes for the diagnosis of ischemic enterocolitis in vivo was examined in an experimental model of ischemia in dogs. A 30-cm segment of small intestine was devascularized by ligating the arteries and veins from the last arcade in 7 dogs. A sham operation was performed in 3 control dogs. 111In oxine-labeled autologous white blood cells were infused 3.5 hours after operation. Anterior and lateral nuclear scanning was performed at 6 and 24 hours postinfusion with a gamma camera equipped with a low-energy magnifying multihole collimator. The animals were killed after 24 hours. The gross and microscopic appearance of the bowel was evaluated. The radioactivity in the serial specimens of the bowel was measured. In vivo scans were positive (ie, increased uptake in the bowel loop) in all dogs with intestinal ischemia at 6 and 24 hours. No significant uptake was noted in control dogs. Rectilinear scan of the bowel removed at autopsy showed a correlation between the area of infarction and tracer accumulation. In addition, there was a progressive decrease in uptake of 111In oxine from the center of the ischemic lesions to the periphery. Forty percent of the total radioactivity was measured at the center of the lesion, whereas only 6.5% was present at 22.5 cm from the center. Thus the ratio between the ischemic and normal tissue was 10:1 (range, 6.5 to 16). These studies demonstrate that 111In oxine-labeled autologous white blood cells can be used for the diagnosis of ischemic enterocolitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Altered diastolic function in asymptomatic infants of mothers with gestational diabetes.

Left and right ventricular filling was studied prospectively in 50 full-term (39.4 +/- 1.3 wk) asymptomatic newborns of mothers with gestational diabetes mellitus (GDM). Their data were compared with those of 80 asymptomatic full-term (39.8 +/- 1.2 wk) infants who served as control subjects. Infants were examined in the immediate newborn period (less than 48 h) and then again at 2-4 and 6-9 wk. Although mean weight, length, and gestational age did not differ, the mean +/- SD left ventricular dimensions during diastole (1.73 +/- 0.15 vs. 1.81 +/- 0.18 cm, P = 0.007) and systole (1.22 +/- 0.15 vs. 1.31 +/- 0.17 cm, P = 0.004) were significantly lower in infants of mothers with GDM compared with control infants. Diastolic measurements suggested a shift from the early diastolic filling of the ventricle to the later period of atrial systole in infants of mothers with GDM. A lower initial one-third area fraction and a higher peak flow velocity and velocity time integral during atrial systole were noted at the mitral valve in infants of mothers with GDM. These changes had resolved by 2-4 wk of age. The altered diastolic filling patterns in infants of mothers with GDM indicate poor myocardial relaxation and/or decreased passive compliance of the ventricular myocardium. These alterations were observed in asymptomatic infants in the absence of left ventricular or septal hypertrophy. If exposed to significant stress such as asphyxia or sepsis, the observed myocardial dysfunction could lead to higher morbidity in these infants.

Adult↗