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

Katz, H.; Butler, Peter C.; Homan, M.; Zerman, A.; Caumo, Andrea; Cobelli, Claudio; Rizza, Robert A.

doi:10.1152/ajpendo.1993.264.4.e561

Cited by 25 publications

(19 citation statements)

References 25 publications

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“…At steady state, hepatic glucose release is greater and glucose uptake is lower in diabetic than nondiabetic subjects. However, limited information is available regarding the rate of response to insulin in humans due in large part to difficulties in the past in measurement of glucose turnover under non-steady state conditions (15,(28)(29)(30). The slower rate of increase in glucose disappearance in the diabetic subjects is consistent with results previously reported by DeFronzo et al using the limb catheterization technique (10).…”

Section: Diabeticsupporting

confidence: 81%

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

Turk¹,

Alzaid

Dinneen

et al. 1995

J. Clin. Invest.

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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 '4CO2 into glucose were measured during 0.5 and 1.0 mU/kg-' per min-' insulin infusions while glucose was clamped at -95 mg/dI 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 "4CO2 (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. (J. Clin. Invests 1995. 95:755-762.) Key words: insulin resistance . gluconeogenesis * glucose turnover * rate of onset of insulin action

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Section: Diabeticsupporting

confidence: 81%

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

Turk¹,

Alzaid

Dinneen

et al. 1995

J. Clin. Invest.

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“…We achieved our goal of clamping the blood glucose in the fasting range, but with some discrepancies in matching the baseline levels of insulin and glucagon to fasting concentrations of these hormones; average plasma glucagon and insulin concentrations for the group were 15-20% higher than in the fasting state. The variation between fasting and baseline levels of insulin and glucagon likely accounts for the wide range and higher average rate of steady-state R a and R d in our subjects relative to values that are commonly observed for normal fasting subjects (7,23). In fact, there was a strong correlation between the differences in fasting and clamped insulin and glucagon concentrations and the steady-state glucose R a ; the greater the difference in clamped to fasting hormone levels the higher the R a (r ϭ 0.59 for insulin and 0.60 for glucagon).…”

Section: Discussionmentioning

confidence: 84%

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Prigeon

Quddusi²,

Paty³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

183

129

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. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003 10.1152/ ajpendo.00024.2003.-Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (R a) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [ 3 H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 Ϯ 14 vs. 113 Ϯ 11 pM; 0.153 Ϯ 0.029 vs. 0.156 Ϯ 0.026 nM; and 64.7 Ϯ 11.5 vs. 65.8 Ϯ 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steadystate levels of 4.8 Ϯ 0.2 to a nadir of 4.1 Ϯ 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in R a, from 22.6 Ϯ 2.8 to 19.1 Ϯ 2.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance GLUCAGON-LIKE PEPTIDE-1 (GLP-1; 7-36 amide) is an intestinal hormone that plays an important role in glucose homeostasis. GLP-1 is a potent insulinotropin that is secreted after meal ingestion, thereby contributing to the incretin effect (the greater insulin release occurring after oral compared with intravenous glucose administration; see Refs. 9, 28, and 35). GLP-1 also decreases glucagon release, either through direct interaction with the ␣-cell or indirectly via stimulation of insulin and somatostatin secretion (10, 47). Thus the overall effect of GLP-1 on pancreatic islet secretion is to decrease circulating glucose concentrations. In addition to the regulation of islet hormones, GLP-1 slows gastric emptying (49), another action that attenuates the rise in plasma glucose after meal ingestion. This broad range of acute effects on processes governing circulating levels of glucose has stimulated interest in using GLP-1 or GLP-1 analogs for the treatment of diabetes.Many investigators have also suggested that GLP-1 has effects on glucose metabolism beyond the regulation of pancreatic islet hormone secretion, e.g., extrapancreatic effects. The first report was from Gutniak and colleagues (20)...

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“…In this regard, it is important to note that the insulin concentrations present during the so-called high-dose insulin study fall on the lower portion of the insulin dose-response curve for stimulation of glucose uptake (8,9,58). Early saturation of transport could result from a decrease in the number or function of membrane-bound glucose transporters.…”

Section: A B D Cmentioning

confidence: 99%

“…We chose to study "basal" insulin concentration because this potentially provides insight into the effects of glucose after an overnight fast and because this is the insulin concentration at which the widely used minimal model estimates glucose effectiveness (13). We chose the high-dose insulin infusion because it results in insulin concentrations that fall on the lower portion of the insulin dose-response curve for the stimulation of glucose uptake (8,9,58) and that approximate insulin concentrations frequently observed after eating a mixed meal (1-3). As previously discussed in detail (22,23), we chose to individually determine appropriate "basal" insulin concentration (defined as that required to maintain euglycemia) for each subject on each study day.…”

Section: A B D Cmentioning

confidence: 99%

Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake.

et al. 1998

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The present studies were undertaken to determine whether people with type 2 diabetes are resistant to the effects of glucose as well as insulin. Diabetic and nondiabetic subjects were studied on three occasions. Hormone secretion was inhibited with somatostatin. Insulin concentrations were kept at "basal" levels (referred to as low insulin infusion) from 0 to 180 min then increased to ~200 pmol/l from 181 to 360 min (referred to as high insulin infusion). 3 H]glucose) and incorporation of 1 4 C O 2 into glucose (an index of gluconeogenesis) in both diabetic and nondiabetic subjects, indicating normal hepatic (and perhaps renal) response to glucose. In the nondiabetic subjects, an increase in glucose concentration from 95 to 130 to 165 mg/dl resulted in a progressive increase in glucose disappearance during both the low (19.9 ± 1.8 to 23.6 ± 1.8 to 25.4 ± 1.6 µmol · kg -1 · min -1 ; P = 0.003 by ANOVA) and high (36.4 ± 3.1 to 47.6 ± 4.5 to 61.1 ± 7.0 µmol · kg -1 · min -1 ; P = 0.001 by ANOVA) insulin infusions. In contrast, in the diabetic subjects, whereas an increase in glucose from 95 to 130 mg/dl resulted in an increase in glucose disappearance during both the low (P = 0.001) and high (P = 0.01) dose insulin infusions, a further increase in glucose concentration to 165 mg/dl had no further effect (P = 0.41 and 0.38) on disappearance at either insulin dose (low: 14.2 ± 0.8 to 18.2 ± 1.1 to 18.7 ± 2.4 µmol · kg -1 · m i n -1 ; high: 21.0 ± 3.2 to 33.9 ± 6.4 to 32.5 ± 8.0 µmol · k g -1 · min -1 for 95, 130, and 165 mg/dl, respectively). We conclude that whereas glucose-induced stimulation of its own uptake is abnormal in type 2 diabetes, glucoseinduced suppression of endogenous glucose production and output is not. The abnormality in uptake occurs in the presence of both basal and high insulin concentrations and is evident at glucose concentrations above but not below 130 mg/dl, implying a defect in a glucoseresponsive step. D i a b e t e s 47:1735-1747, 1998

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

Cited by 25 publications

References 25 publications

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

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

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake.

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