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Biomedical subjects

R Rizza

Publications and source records attributed to R Rizza.

At least 19 recordsLinked to original sources
PubMed1999

Impact of lack of suppression of glucagon on glucose tolerance in humans.

People with type 2 diabetes have defects in both alpha- and beta-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a "prandial" glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic (n = 10) or diabetic (n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng. kg(-1). min(-1), beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the "diabetic" insulin profile, lack of glucagon suppression resulted in a marked increase (P < 0.002) in both the peak glucose concentration (11.9 +/- 0.4 vs. 8.9 +/- 0.4 mmol/l) and the area above basal of glucose (927 +/- 77 vs. 546 +/- 112 mmol. l(-1). 6 h) because of impaired (P < 0.001) suppression of glucose production. In contrast, during the "nondiabetic" insulin profile, lack of suppression of glucagon resulted in only a slight increase (P < 0.02) in the peak glucose concentration (9.1 +/- 0.4 vs. 8.4 +/- 0.3 mmol/l) and the area above basal of glucose (654 +/- 146 vs. 488 +/- 118 mmol. l(-1). 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

Adult↗
PubMed1997

Effects of hepatic glycogen content on hepatic insulin action in humans: alteration in the relative contributions of glycogenolysis and gluconeogenesis to endogenous glucose production.

Hepatic glycogen content varies by almost 2-fold during the day, generally increasing from a nadir before breakfast to a peak 4-5 h after supper. To determine whether differences in hepatic glycogen content of this magnitude alter hepatic insulin action, nine subjects were studied on two occasions. On one occasion saline was infused, whereas on the other occasion an infusion of glucose [16.4 micromol/kg lean body mass (-lbm) x min] was started immediately after supper and continued throughout the night so as to spare hepatic glycogen. The nocturnal glucose infusion resulted in higher (P < 0.05) plasma glucose (6.0 +/- 0.1 vs. 5.1 +/- 0.1 mmol/L) and insulin (127 +/- 38 vs. 49 +/- 9 pmol/L) concentrations, and lower (P < 0.05) plasma glucagon concentrations (74 +/- 11 vs. 97 +/- 20 pg/mL) than did saline infusion. As anticipated, endogenous glucose production (EGP) was substantially lower (P < 0.001) during the glucose than during the saline infusion (7.0 +/- 0.9 vs. 19.4 +/- 1.3 micromol/kg-lbm x min). After discontinuation of the glucose infusion, glucose and insulin concentrations fell to levels that no longer differed from those observed during the saline infusion. In contrast, EGP increased to rates that were higher (P < 0.05) than those observed over the same interval after overnight saline infusion (19.2 +/- 1.2 vs. 16.5 +/- 0.7 micromol/kg-lbm x min). Despite higher EGP, the rate of incorporation of 14CO2 into glucose was lower (P < 0.001) after glucose than that after saline infusion (9.8 +/- 1.2% vs. 24.4 +/- 3.0%), implying a reciprocal relationship between hepatic glycogen content and gluconeogenesis. On the other hand, when differences in basal rates were taken into account, insulin-induced suppression of both EGP and incorporation of 14CO2 into glucose did not differ on the two occasions. Thus, whereas hepatic glycogen content influences both the absolute rate of EGP and the percent contribution of gluconeogenesis to EGP, it does not alter hepatic insulin action.

Blood Glucose↗
PubMed1996

The role of splanchnic glucose appearance in determining carbohydrate tolerance.

Postprandial hyperglycaemia in patients with Type 1 and Type 2 is now well-established. Studies of glucose turnover in these patients have shown that this results from a combination of excessive endogenous glucose production and a lack of appropriate stimulation of glucose uptake. In the case of patients with Type 2 diabetes, this may in part be due to a delay in the increase of plasma insulin concentrations. It may be concluded then that agents which delay the absorption of glucose in the postprandial period may help to improve glycaemic control in patients with diabetes by improving the match between meal-derived glucose appearance and the period of insulin availability.

Blood Glucose↗
PubMed1995

Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM.

Carbohydrate ingestion results in a fall in glucagon concentration in non-diabetic but not in diabetic individuals. To determine if, and the mechanism by which, lack of postprandial suppression of glucagon contributes to hyperglycaemia, nine subjects with insulin-dependent diabetes mellitus (IDDM) ingested 50 g of glucose containing both [2-3H] glucose and [6-3H] glucose on two occasions. [6-14C] glucose, insulin and low-dose somatostatin were infused intravenously at the same rates on both occasions. A basal glucagon infusion was started either at the same time ("constant glucagon") or 2 h following ("suppressed glucagon") glucose ingestion. This resulted in lower (p < 0.001) glucagon concentrations during the first 2 h of the suppressed than during the constant glucagon study days (63 +/- 1 vs 108 +/- 2 pg/ml). Lack of suppression of glucagon led to higher (p < 0.01) postprandial glucose concentrations (10.3 +/- 0.9 vs 8.1 +/- 0.7 mmol/l) and a greater (p < 0.02) integrated glycaemic response. The excessive rise in glucose was due to higher (p < 0.02) rates of postprandial hepatic glucose release during the constant than during the suppressed glucagon study days, whether measured using either [6-3H] glucose (2.6 +/- 0.2 vs 2.0 +/- 0.2 mmol.kg-1 per 6 h) or [2-3H] glucose (3.0 +/- 0.3 vs 2.4 +/- 0.2 mmol.kg-1 per 6 h) as the meal tracer. Glucose disappearance, initial splanchnic glucose clearance and hepatic glucose cycling did not differ on the two occasions. Thus, the present studies demonstrate that lack of postprandial suppression of glucagon, by increasing hepatic glucose release, contributes to hyperglycaemia in subjects with IDDM.

Adult↗
PubMed1995

Effects of the normal nocturnal rise in cortisol on carbohydrate and fat metabolism in IDDM.

Plasma cortisol concentrations increase approximately three- to five-fold during sleep in healthy humans. To determine the effects of the normal nocturnal rise in cortisol on carbohydrate and fat metabolism independent of changes in endogenous insulin secretion, we studied the disposition of a mixed meal in individuals with insulin-dependent diabetes mellitus (IDDM) in whom the normal nocturnal rise in cortisol had been either prevented or mimicked by using metyrapone and a constant or variable hydrocortisone infusion. Insulin was infused intravenously on both occasions in amounts sufficient to create relative postprandial insulin deficiency. The nocturnal rise in cortisol resulted in an approximately 30 mg/dl greater (P < 0.001) peak postprandial glycemic excursion due to greater (P < 0.01) systemic glucose appearance and inappropriately low (P < 0.05) tissue glucose uptake. The latter was most evident when postprandial glucose concentrations in the presence and absence of the nocturnal rise in cortisol were matched by means of an exogenous glucose infusion to avoid the confounding effects of differences in glycemia. The nocturnal rise in cortisol also resulted in increased (P < 0.01) incorporation of 14CO2 into glucose (an index of gluconeogenesis), decreased (P < 0.05) carbohydrate oxidation, and increased (P < 0.05) rates of palmitate appearance, lipid oxidation, and beta-hydroxybutyrate concentrations. Thus the normal nocturnal rise in cortisol, independent of changes in insulin secretion, is an important regulator of postabsorptive and postprandial carbohydrate, fat, and ketone body metabolism in humans.

Adult↗
PubMed1995

Glucose turnover in presence of changing glucose concentrations: error analysis for glucose disappearance.

The present studies were undertaken to determine whether 1) the cold- and hot-GINF techniques used with Steele's model provide equivalent estimates of the rates of glucose appearance (R(a)) and disappearance (R(d)) in the presence of physiological changes in glucose and insulin concentrations, 2) the conditions for the best estimation of R(a) are the same as those for R(d), 3) the magnitude of error (if present) differs in diabetic and nondiabetic subjects, and 4) situations exist in which the knowledge of R(d) allows inferences to be made on whole body glucose uptake. To do so we performed experiments in non-insulin-dependent diabetes mellitus and nondiabetic subjects using simultaneous infusions of [6-3H]glucose and [6-14C]glucose; glucose and insulin were infused to mimic normal postprandial glucose and insulin profiles; the infused glucose contained [6-14C]glucose but not [6-3H]glucose. Compared with the hot-GINF method, the traditional cold-GINF method underestimated (P < 0.05) R(a) and R(d) by 10-15% and hepatic glucose release by 25-50% during the 1st h of the study, with the magnitude of error being the same in both diabetic and nondiabetic subjects. Error analysis demonstrated that errors in R(a) and R(d) have different analytic expressions containing common structural but different volume errors. Both R(a) and R(d) can be accurately measured in diabetic and nondiabetic subjects if glucose specific activity is kept constant and the volume of the accessible pool is used to calculate glucose disappearance. The relationship between R(d) and whole body glucose uptake was also derived. Although R(d) can be determined by relying on measurements in the accessible pool only, the assessment of whole body glucose uptake requires a model of the nonaccessible portion of the glucose system. However, knowledge of R(d) can provide useful insights into the behavior of whole body glucose uptake.

Adult↗
PubMed1995

The effects of non-insulin-dependent diabetes mellitus on the kinetics of onset of insulin action in hepatic and extrahepatic tissues.

The mechanism(s) of insulin resistance in non-insulin-dependent diabetes mellitus remains ill defined. The current studies sought to determine whether non-insulin-dependent diabetes mellitus is associated with (a) a delay in the rate of onset of insulin action, (b) impaired hepatic and extrahepatic kinetic responses to insulin, and (c) an alteration in the contribution of gluconeogenesis to hepatic glucose release. To answer these questions, glucose disappearance, glucose release, and the rate of incorporation of 14CO2 into glucose were measured during 0.5 and 1.0 mU/kg-1 per min-1 insulin infusions while glucose was clamped at approximately 95 mg/dl in diabetic and nondiabetic subjects. The absolute rate of disappearance was lower (P < 0.05) and the rate of increase slower (P < 0.05) in diabetic than nondiabetic subjects during both insulin infusions. In contrast, the rate of suppression of glucose release in response to a change in insulin did not differ in the diabetic and nondiabetic subjects during either the low (slope 30-240 min:0.02 +/- 0.01 vs 0.02 +/- 0.01) or high (0.02 +/- 0.00 vs 0.02 +/- 0.00) insulin infusions. However, the hepatic response to insulin was not entirely normal in the diabetic subjects. Both glucose release and the proportion of systemic glucose being derived from 14CO2 (an index of gluconeogenesis) was inappropriately high for the prevailing insulin concentration in the diabetic subjects. Thus non-insulin-dependent diabetes mellitus slows the rate-limiting step in insulin action in muscle but not liver and alters the relative contribution of gluconeogenesis and glycogenolysis to hepatic glucose release.

Alanine↗
PubMed1994

The dual tracer time-varying volume method for measuring hepatic glucose release in nonsteady state: theoretical and simulation results.

Measurement of hepatic glucose release in nonsteady state is difficult and experimental approaches have been developed in order to circumvent Steele's model inadequacy. Recently, a resurgence of interest in the time-varying volume method developed by Issekutz has taken place. Issekutz's approach assumes that the volume of Steele's model is not constant but time-varying and that its time course can be measured by infusing two tracers with different patterns. The time-varying volume is then substituted into Steele's equation and hepatic glucose release is estimated. The aim of this study was to analyze some basic aspects of Issekutz's method and to determine the accuracy of its estimate of hepatic glucose release. A theoretical analysis showed that the time-varying volume measured by Issekutz's approach is not unique but depends on the format of administration of the two tracers. In addition, such a volume allows an accurate estimate of hepatic glucose release if one of the two tracers is infused in such a way that its specific activity is maintained perfectly constant during the experiment. Since it is impossible to achieve a perfect clamp of specific activity, we also evaluated the performance of Issekutz's approach in more realistic experimental conditions which were reproduced by resorting to computer simulation. We simulated a euglycaemic clamp with insulin rising from basal to a plateau of approximately 40 microU/ml and then returning to basal. Nonsteady-state glucose kinetics were described by a previously validated two-compartment model while the time course of hepatic glucose release was derived from the literature. Both noise-free and noisy experimental conditions were simulated. We showed that the degree of accuracy of Issekutz's approach is very good and better than the one associated with the hot-ginf method. On the other hand, the major problem with Issekutz's approach is the sensitivity of the volume estimate to the measurement noise, which may limit its applicability in practice. In conclusion, we elucidated the theoretical grounds of Issekutz's approach and assessed its performance during nonsteady state in a realistic scenario using computer simulation.

Body Fluid Compartments↗
PubMed1994

Assessment of insulin action in NIDDM in the presence of dynamic changes in insulin and glucose concentration.

Both glucose and insulin are important regulators of glucose uptake and hepatic glucose release. Because insulin concentrations rarely if ever increase under daily living conditions, unless glucose concentrations also increase, we sought to determine whether hepatic and extrahepatic responses to changes in insulin and glucose concentration are impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). To address this question, glucose metabolism was measured in diabetic and nondiabetic subjects. A computer-driven infusion system was used to produce a nondiabetic postprandial insulin profile in both groups while sufficient exogenous glucose was infused to mimic nondiabetic postprandial glucose concentrations. Although NIDDM was associated with greater (P < 0.05) hepatic glucose release both before and during the prandial insulin infusion, suppression did not differ in the diabetic and nondiabetic subjects (-1.06 +/- 0.20 vs. -0.86 +/- 0.15 mmol/kg every 4 h). In contrast, stimulation of both glucose disappearance (0.77 +/- 0.27 vs. 1.68 +/- 0.27 mmol/kg every 4 h) and forearm glucose uptake (187 +/- 81 vs. 550 +/- 149 mumol/dl every 4 h) was lower (P < 0.05) in diabetic than in nondiabetic subjects. Thus, despite increased basal rates of glucose production, obese individuals with NIDDM had decreased stimulation of glucose disappearance but normal suppression of hepatic glucose release in response to nondiabetic prandial glucose and insulin concentrations. These data indicate that the increase in glucose that occurs with carbohydrate ingestion is likely to compensate for hepatic but not extrahepatic insulin resistance.

Blood Glucose↗
PubMed1993

Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error.

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.

Adult↗
PubMed1993

Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans.

Glucocorticoid concentrations vary throughout the day. To determine whether an increase in cortisol similar to that present during sleep is of physiologic significance in humans, we studied the disposition of a mixed meal when the nocturnal rise in cortisol was mimicked or prevented using metyrapone plus either a variable or constant hydrocortisone infusion. When glucose concentrations were matched with a glucose infusion, hepatic glucose release (2.6 +/- 0.2 vs. 1.5 +/- 0.4 nmol/kg per 6 h) was higher (P < 0.05) while glucose disappearance (5.9 +/- 0.3 vs. 7.3 +/- 0.9 mmol/kg per 6 h) and forearm arteriovenous glucose difference (64 +/- 24 vs. 231 +/- 62 mmol/dl per 6 h) were lower (P < 0.05) during the variable than basal infusion. The greater hepatic response during the variable cortisol infusion was mediated (at least in part) by inhibition of insulin and stimulation of glucagon secretion as reflected by lower (P < 0.05) C-peptide (0.29 +/- 0.01 vs. 0.38 +/- 0.04 mmol/liter per 6 h) and higher (P < 0.05) glucagon (42.7 +/- 2.0 vs. 39.3 +/- 1.8 ng/ml per 6 h) concentrations. In contrast, the decreased rates of glucose uptake appeared to result from a state of "physiologic" insulin resistance. The variable cortisol infusion also increased (P < 0.05) postprandial palmitate appearance as well as palmitate, beta-hydroxybutyrate, and alanine concentrations, suggesting stimulation of lipolysis, ketogenesis, and proteolysis. We conclude that the circadian variation in cortisol concentration is of physiologic significance in normal humans.

Adult↗
PubMed1992

Use of [3-3H]glucose and [6-14C]glucose to measure glucose turnover and glucose metabolism in humans.

[3-3H]glucose is frequently used to measure glucose turnover in humans. If fructose 6-phosphate-fructose 1,6-diphosphate cycling (Fpc) is negligible in both liver and muscle, then [3-3H]- and [6-14C]glucose (corrected for Cori cycle activity) should provide equivalent measures of glucose turnover. In addition, if glycogenolysis is fully suppressed, then [14C]lactate specific activity should equal that of [6-14C]glucose from which it was derived, and oxidation of [6-14C]glucose, as measured by rate of generation of 14CO2, should equal total glucose oxidation (i.e., that derived from intra- and extracellular pools) as measured by indirect calorimetry. To address these questions, glucose turnover was measured simultaneously with [3-3H]- and [6-14C]glucose in the basal state and in presence of low (approximately 200 pM) and high (approximately 750 pM) insulin concentrations. Glucose turnover rates measured with [3-3H]- and [6-14C]glucose were equivalent at all insulin concentrations, indicating that Fpc had no detectable effect on measurement of glucose appearance. [14C]lactate specific activity was lower (P less than 0.01) than that of [6-14C]glucose in the basal state but not during either low- or high-dose insulin infusion, implying that all lactate was derived from extracellular glucose. On the other hand, glucose oxidation as measured by rate of generation of 14CO2 was lower (P less than 0.05) than glucose oxidation as measured by indirect calorimetry during both insulin infusions, implying either that suppression of glycogenolysis was not complete in all tissues or that one or both of these techniques do not accurately measure glucose oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effects of pancreas transplantation on postprandial glucose metabolism.

BACKGROUND: Because a pancreas allograft is placed in the pelvis, pancreas transplantation abolishes the normal gradient between portal-vein and peripheral-vein insulin concentrations and causes systemic hyperinsulinemia. Whether pancreas transplantation restores carbohydrate metabolism to normal is not known. METHODS: We studied seven patients with insulin-dependent diabetes mellitus after pancreas-kidney transplantation, seven nondiabetic patients after kidney transplantation (to control for immunosuppression), and eight normal subjects. Measurements were made after an overnight fast and after ingestion of a mixed meal. RESULTS: Although plasma glucose concentrations did not differ in the two transplant groups, plasma insulin concentrations were significantly higher in the diabetic pancreas-kidney recipients than in the nondiabetic kidney recipients, both before the meal (mean +/- SE, 102 +/- 15 vs. 53 +/- 6 pmol per liter; P less than 0.05) and afterward (123 +/- 22 vs. 61 +/- 6 nmol per liter per six hours; P less than 0.05). Plasma C-peptide concentrations were the same in both groups, indicating that hyperinsulinemia was due to decreased insulin clearance rather than increased insulin secretion. Despite drainage of the venous effluent from the transplanted pancreas into the systemic circulation, the values for splanchnic clearance of ingested glucose, suppression of hepatic glucose release, incorporation of carbon dioxide into glucose, stimulation of glucose oxidation, glucose uptake, and forearm glucose clearance were all similar in the transplant groups and differed minimally from the values in the normal group. The similar rates of glucose uptake in the presence of higher systemic insulin concentrations indicated that the extrahepatic tissues of the diabetic pancreas-kidney recipients were insulin-resistant. CONCLUSIONS: Despite systemic delivery of insulin, pancreas-kidney transplantation in patients with diabetes results in carbohydrate metabolism similar to that in nondiabetic subjects receiving the same immunosuppressive agents after kidney transplantation.

Adult↗
PubMed1991

Effects of chronic systemic insulin delivery on insulin action in dogs.

The metabolic consequences of the prolonged systemic insulin delivery associated with human pancreas transplantation have not been precisely defined. To determine if systemic insulin delivery in the absence of immunosuppressive agents results in alterations in hepatic or extrahepatic insulin action, three groups of dogs were studied 2 months after either a sham operation or after their pancreatic venous drainage was severed and anastomosed to the inferior vena cava or portal vein (sham, peripheral and portal groups, respectively). The pattern of venous drainage was documented by measuring vena cava and portal insulin concentrations before and after glucose injection. Systemic insulin concentrations were higher (p less than 0.05) in the peripheral group than in the portal group both following a 14-h fast and after intravenous glucose. During a hyperinsulinaemic euglycaemic clamp (1 mU.kg-1.min-1), glucose utilization (measured using [6(3)H]glucose) was slightly lower (p = 0.07) in the peripheral than in the portal group. Hepatic glucose release was equal in all groups. Carbon dioxide incorporation into glucose (an estimate of gluconeogenesis) was higher in the portal than peripheral group in the fasted state but not during insulin infusion. Plasma concentrations and flux rates of fatty acids and amino acids did not differ between groups. We conclude that chronic systemic insulin delivery results in a) systemic but not portal hyperinsulinaemia, b) a minimal impairment in insulin-stimulated glucose uptake, without altering insulin-induced suppression of hepatic glucose release, and c) no effect on fatty acid or amino acid turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Mechanism of growth hormone-induced postprandial carbohydrate intolerance in humans.

Growth hormone excess can cause postprandial carbohydrate intolerance. To determine the contribution of splanchnic and extrasplanchnic tissues to this process, subjects were fed an isotopically labeled mixed meal after either a 12-h infusion of saline or growth hormone (4 micrograms.kg-1.h-1 [corrected]). Growth hormone infusion resulted in higher glucose and insulin concentrations both before and after meal ingestion. Despite growth hormone-induced hyperglycemia and hyperinsulinemia, postprandial hepatic glucose release and carbon dioxide incorporation into glucose (a qualitative estimate of gluconeogenesis) were similar to those present during saline, suggesting altered hepatic regulation. This was confirmed when glucose was infused in the absence of growth hormone to achieve glucose (and insulin) concentrations comparable to those present during growth hormone infusion. Although growth hormone excess did not alter splanchnic uptake of ingested glucose, it resulted in a fivefold increase in postprandial hepatic glucose release (578 +/- 31 vs. 117 +/- 10 mg.kg-16 h-1, P less than 0.01), less suppression of carbon dioxide incorporation into glucose (-13 +/- 9 vs. -53 +/- 12 mg.kg-1. 6-h-1, P less than 0.01), and lower glucose uptake (1,130 +/- 59 vs. 1,850 +/- 150 mg.kg-1.6 h-1, P less than 0.01). The decrease in postprandial glucose uptake did not appear to be mediated by a change in substrate uptake since postprandial plasma concentrations and forearm balance of lactate, free fatty acids, and ketone bodies did not differ in the presence and absence of growth hormone excess.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1990

Insulin resistance in type II diabetes mellitus.

In vivo studies indicate that patients with NIDDM have defects in both insulin secretion and insulin action. The decrease in insulin action is due to both hepatic and extrahepatic insulin resistance. The impairment in glucose uptake is associated with alterations in both oxidative and nonoxidative disposal. Defective glucose transport may limit both of these processes. NIDDM also is associated with increased concentrations and rates of oxidation of plasma free fatty acids. Insulin resistance appears to be familial and in at least some individuals antedates glucose intolerance. In vitro studies indicate that insulin resistance can involve a variety of insulin sensitive tissues including adipocytes, muscle and liver. While most studies note that insulin binding and insulin receptor kinase activity are decreased in insulin sensitive tissues in obese patients with NIDDM, further delineation of the contribution of obesity and diabetes is required. Alterations in glucose transporter number and function likely account at least in part for impaired glucose transport. The cause of the alterations in other insulin responsive pathways and the role of an abnormal metabolic milieu versus intrinsic cellular defects remain to be established.

Adipose Tissue↗
PubMed1990

Choice and use of tracers.

The isotope dilution method has been widely employed to measure glucose turnover in man. The validity of this technique depends upon several assumptions. First, it is assumed that the selected model of glucose kinetics is valid. Under nonsteady state conditions this has recently been challenged for the most commonly used single compartment model. Secondly, it is assumed that the isotope is metabolized in the same manner as unlabeled glucose. If the isotope loses its label when subject to a substrate cycle (for example, [2-3H]glucose in glucose to glucose 6-phosphate cycling), an overestimate of glucose disposal will result. In contrast, if isotope that has been cleared (for example [6-3H]glucose in hepatic glucogen) is recycled into the systemic circulation, an underestimation of glucose turnover will result. Thirdly, it is assumed that measurement of specific activity is accurate. It has recently been shown that many commercially available tritiated (but not 14C) isotopes contain radioactive nonglucose contaminants which have a slower clearance rate than glucose under conditions of high glucose turnover. This can result in overestimates of specific activity and underestimates of glucose appearance, leading to calculated negative hepatic glucose release. While this problem may be avoided with purified tritiated glucose tracers, a similar problem with stable isotopes of glucose remains to be determined. In summary, the choice of glucose isotope should reflect the probability of substrate cycling and isotope cycling in the experiment in question. Care should be taken to ensure purified isotopes are selected and that the model of glucose kinetics used is valid during the conditions to be studied.

Animals↗