Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans.

Alzaid, Aus; Dinneen, Seán F.; Turk, D.; Caumo, Andrea; Cobelli, Claudio; Rizza, Robert A.

doi:10.1172/jci117599

Cited by 76 publications

(57 citation statements)

References 60 publications

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“…Our results may appear to contradict those of Baron et al [16] and Alzaid et al [55], who concluded that the mass action effect of glucose is normal in NIDDM subjects. However, there were several differences between their experimental protocols [16,55] and our own.…”

Section: Discussioncontrasting

confidence: 99%

“…However, there were several differences between their experimental protocols [16,55] and our own. In Baron's study [16] fasting hyperglycaemia was clamped during suppression of plasma insulin levels by somatostatin infusion and glucose turnover measurements were obtained with tracer technique.…”

Section: Discussionmentioning

confidence: 87%

“…However, the effect of induced insulinopenia rather than the ability of increasing concentration of plasma glucose concentration on glucose disposal was assessed. Alzaid et al [55] determined insulin-mediated glucose uptake in NIDDM and non-diabetic subjects at glucose concentrations clamped at either 5 mmol/l (euglycaemia) or at plasma glucose levels varying to mimic glucose profile after food ingestion. In both experiments insulin was infused so as to simulate a 'non-diabetic' postprandial profile.…”

Section: Discussionmentioning

confidence: 99%

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Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

et al. 1997

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Tissue glucose uptake occurs via a facilitated transport system [1]. The major factors that regulate glucose uptake in vivo are the prevailing plasma glucose and insulin concentrations. Following glucose ingestion the plasma glucose concentration rises, insulin secretion is stimulated and the combination of hyperglycaemia and hyperinsulinaemia contributes to the increase in glucose utilization. Plasma glucose concentration influences glucose utilization by a mass Diabetologia (1997) Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-3 H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 m mol/kg ⋅ min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 m mol/kg ⋅ min), and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 m mol/kg ⋅ min) glucose disposal was lower during all three steps (p < 0.05-0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 m mol/kg ⋅ min) only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8 ± 1.7 m mol/kg ⋅ min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 m mol/kg ⋅ min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ± 1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 m mol/kg ⋅ min; p < 0.05-0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687-697] Keywords Hyperglycaemia, mass action effect, glucose-mediated glucose metabolism, glucose oxidation, non-oxidative glucose metabol...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

et al. 1997

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“…Furthermore, in NIDDM, the importance of glucose effectiveness to glucose tolerance may be substantial. Insulin secretion is suppressed (26), and insulin resistance is usually profound, such that within the physiologic concentration range insulin has little measurable effect to increase R d (27,28). Thus it follows that glucose effectiveness is the primary determinant of R d in the type 2 diabetic state (29), as confirmed by Alzaid and colleagues (27) from meal tolerance studies in which glucose balance across muscle bed were assessed.…”

Section: Discussionmentioning

confidence: 90%

Glucose effectiveness assessed under dynamic and steady state conditions. Comparability of uptake versus production components.

Ader¹,

Ni²,

Bergman³

1997

J. Clin. Invest.

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Glucose tolerance is determined by both insulin action and insulin-independent effects, or "glucose effectiveness," which includes glucose-mediated stimulation of glucose uptake (R d ) and suppression of hepatic glucose output (HGO). Despite its importance to tolerance, controversy surrounds accurate assessment of glucose effectiveness. Furthermore, the relative contributions of glucose's actions on R d and HGO under steady state and dynamic conditions are unclear. We performed hyperglycemic clamps and intravenous glucose tolerance tests in eight normal dogs, and assessed glucose effectiveness by two independent methods. During clamps, glucose was raised to three successive 90-min hyperglycemic plateaus by variable labeled glucose infusion rate; glucose effectiveness (GE) was quantified as the slope of the dose-response relationship between steady state glucose and glucose infusion rate (GE CLAMP (

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“…This was done in an effort to minimize the change in plasma glucose specific activity, thereby enabling accurate measurement of glucose turnover (3,15). This resulted in a mean plasma glucose specific activity that averaged Ϫ3.2 Ϯ 11.2, 4.7 Ϯ 7.0, and 15.1 Ϯ 4.7% of basal on the euglycemia, sustained-hyperglycemia, and profile study days, respectively.…”

Section: Subjectsmentioning

confidence: 99%

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

Vella¹,

Reed²,

Charkoudian³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Glucoseinduced suppression of endogenous glucose production: dynamic response to differing glucose profiles. Am J Physiol Endocrinol Metab 285: E25-E30, 2003. First published March 11, 2003 10.1152/ajpendo.00530.2002To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon (ϳ130 ng/l) and insulin (ϳ65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at ϳ5.3 mM (euglycemia), ϳ7.0 mM (sustained hyperglycemia; n ϭ 10), or varied to create a "postprandial" profile (profile; n ϭ 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 Ϯ 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 Ϯ 1.21 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 . On the profile study day, glucose increased to a peak of 11.2 Ϯ 0.5 mmol/l, and EGP decreased to a nadir of 6.79 Ϯ 2.54 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 Ϯ 2.45 vs. 12.11 Ϯ 3.21 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (Ϫ1,952 Ϯ 204 vs. Ϫ1,922 Ϯ 246 mmol ⅐ kg Ϫ1 ⅐ 6 h Ϫ1 ). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP. glucose effectiveness; glucose turnover ENDOGENOUS GLUCOSE PRODUCTION (EGP) is regulated by plasma glucose and insulin concentrations (2,11,12,22,25,27). In the presence of a constant glucose concentration, insulin suppresses glucose production by both direct and indirect mechanisms (11). The direct effects are mediated by activation of hepatic insulin receptors (33). The indirect effects are mediated by multiple factors, including inhibition of glucagon secretion, inhibition of lipolysis, and reduction in the concentration of gluconeogenic precursors (11). Although a change in plasma insulin concentration is accompanied by a reciprocal change in EGP, the effects of insulin are delayed, with suppression lagging behind an increase in plasma insulin and rises in EGP lagging behind a fall in plasma insulin (10). This presumably occurs because of the time required for insulin to activate its receptor and because of the slow rate of equilibration between plasma and muscle/adipose interstitial insulin concentrations (1).The kinetic response of EGP to a change in glucose concentration is less well defined. In the presence of constant insulin concentrations, clamping glucose at a progressively higher concentration results in a progressive decrease in steady-state rates of EGP (2,20,22). Furthermore, EGP decreases when glucose concentration is increased in a pattern mimicking that commonly o...

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Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans.

Cited by 76 publications

References 60 publications

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Glucose effectiveness assessed under dynamic and steady state conditions. Comparability of uptake versus production components.

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles

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