Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange

DeFronzo, Ralph A.; Ferrannini, Eleuterio; Hendler, Rosa; Wahren, John; Felig, Philip

doi:10.1073/pnas.75.10.5173

Cited by 255 publications

(179 citation statements)

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“…Despite all the evidence [1][2][3][4][5][6] indicating that excess adiposity is associated with the impairment of insulinmediated glucose uptake in muscle, the cellular/metabolic mechanisms that explain how an increase in fat mass leads to this derangement are not clear. The lack of clarity concerning the mechanistic link between increased fat mass and muscle insulin resistance is further compounded by evidence that not all overweight/obese individuals are insulin resistant, and that equally obese individuals can be insulin sensitive, as well as insulin resistant [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis

et al. 2007

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Aims/hypothesis The biological mechanism by which obesity predisposes to insulin resistance is unclear. One hypothesis is that larger adipose cells disturb metabolism via increased lipolysis. While studies have demonstrated that cell size increases in proportion to BMI, it has not been clearly shown that adipose cell size, independent of BMI, is associated with insulin resistance. The aim of this study was to test this widely held assumption by comparing adipose cell size distribution in 28 equally obese, otherwise healthy individuals who represented extreme ends of the spectrum of insulin sensitivity, as defined by the modified insulin suppression test. Subjects and methods Subcutaneous periumbilical adipose tissue biopsy samples were fixed in osmium tetroxide and passed through the Beckman Coulter Multisizer to obtain cell size distributions. Insulin sensitivity was quantified by the modified insulin suppression test. Quantitative real-time PCR for adipose cell differentiation genes was performed for 11 subjects. Results All individuals exhibited a bimodal cell size distribution. Contrary to expectations, the mean diameter of the larger cells was not significantly different between the insulin-sensitive and insulin-resistant individuals. Moreover, insulin resistance was associated with a higher ratio of small to large cells (1.66±1.03 vs 0.94±0.50, p=0.01). Similar cell size distributions were observed for isolated adipose cells. The real-time PCR results showed two-to threefold lower expression of genes encoding markers of adipose cell differentiation (peroxisome proliferator-activated receptor γ1 [PPARγ1], PPARγ2, GLUT4, adiponectin, sterol receptor element binding protein 1c) in insulinresistant compared with insulin-sensitive individuals. Conclusions/interpretation These results suggest that after controlling for obesity, insulin resistance is associated with an expanded population of small adipose cells and decreased expression of differentiation markers, suggesting that impairment in adipose cell differentiation may contribute to obesity-associated insulin resistance.

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Section: Introductionmentioning

confidence: 99%

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis

et al. 2007

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“…Insulin levels in excess of 6000 pmol/l, when brought about under euglycaemic conditions, were associated with minimal (4 mmol/kg body weight per min) net splanchnic glucose uptake in human subjects (DeFronzo et al 1978) and only a modest (10 mmol/kg body weight per min) net hepatic glucose uptake in the dog (Frizzell et al 1988). Likewise, increasing the plasma glucose level 2-fold by peripheral intravenous (IV) glucose infusion in the presence of fixed basal amounts of insulin and glucagon caused only slight (3·3 mmol/kg body weight per min) net splanchnic glucose uptake in human subjects (DeFronzo et al 1983) and little net hepatic glucose uptake in the dog (Shulman et al 1978;Adkins et al 1987).…”

Section: Portally Delivered Glucose: the 'Portal Signal'mentioning

confidence: 99%

“…Work carried out in human subjects (DeFronzo et al 1978(DeFronzo et al , 1983Basu et al 2000) and dogs (Shulman et al 1978;Cherrington et al 1979;Barrett et al 1985;Adkins et al 1987;Frizzell et al 1988;McGuinness et al 1990) demonstrates that neither hyperinsulinaemia nor hyperglycaemia can independently cause much net hepatic glucose uptake. Insulin levels in excess of 6000 pmol/l, when brought about under euglycaemic conditions, were associated with minimal (4 mmol/kg body weight per min) net splanchnic glucose uptake in human subjects (DeFronzo et al 1978) and only a modest (10 mmol/kg body weight per min) net hepatic glucose uptake in the dog (Frizzell et al 1988).…”

Section: Portally Delivered Glucose: the 'Portal Signal'mentioning

confidence: 99%

“…The ability of combined changes in insulin and glucose to cause greater hepatic glucose uptake when they are associated with oral glucose delivery led DeFronzo et al (1978) to propose the existence of a gut factor, released in response to oral glucose intake, which could augment net hepatic glucose uptake. Since the proposition of this gut factor, a number of studies have cast doubt on its importance.…”

Section: Portally Delivered Glucose: the 'Portal Signal'mentioning

confidence: 99%

“…In men the combination of hyperglycaemia (9·7-12·5 mM) and hyperinsulinaemia (arterial levels of 240 -330 pmol/l) resulted in a net splanchnic glucose uptake of 5·6 -8·9 mmol/kg body weight per min (DeFronzo et al 1978(DeFronzo et al , 1983Basu et al 2000). Since glucose uptake by the gut accounted for approximately half of that amount, it is clear that little glucose was taken up by the liver, despite the presence of insulin and glucose levels at least as great as those seen after oral glucose consumption.…”

Section: Portally Delivered Glucose: the 'Portal Signal'mentioning

confidence: 99%

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Regulation of hepatic metabolism by enteral delivery of nutrients

et al. 2006

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The liver plays a unique role in nutrient homeostasis. Its anatomical location makes it ideally suited to control the systemic supply of absorbed nutrients, and it is the primary organ that can both consume and produce substantial amounts of glucose. Moreover, it is the site of a substantial fraction (about 25 %) of the body's protein synthesis, and the liver and other organs of the splanchnic bed play an important role in sparing dietary N by storing ingested amino acids. This hepatic anabolism is under the control of hormonal and nutritional changes that occur during food intake. In particular, the route of nutrient delivery, i.e. oral (or intraportal) v. peripheral venous, appears to impact upon the disposition of the macronutrients and also to affect both hepatic and whole-body nutrient metabolism. Intraportal glucose delivery significantly enhances net hepatic glucose uptake, compared with glucose infusion via a peripheral vein. On the other hand, concomitant intraportal infusion of both glucose and gluconeogenic amino acids significantly decreases net hepatic glucose uptake, compared with infusion of the same mass of glucose by itself. Delivery of amino acids via the portal vein may enhance their hepatic uptake, however. Elevation of circulating lipids under postprandial conditions appears to impair both hepatic and whole-body glucose disposal. Thus, the liver's role in nutrient disposal and metabolism is highly responsive to the route of nutrient delivery, and this is an important consideration in planning nutrition support and optimising anabolism in vulnerable patients.

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Measuring Insulin ActionIn Vivo

Bergman

Hücking

Watanabe

2004

International Textbook of Diabetes Mellitus

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The goal to accurately measure insulin sensitivity (i.e., “insulin resistance”) in patients remains an important goal. Insulin resistance is a risk factor for a plethora of chronic diseases (diabetes cardiovascular disease, hypertension, colon cancer). To study these diseases and to intervene early in their pathogenesis requires that we quantify risk factors and insulin resistance is one important candidate. To accurately measure sensitivity it is important to use a method that observes in some fashion the metabolic effect of insulin given intravenously . Thus, the glucose clamp and the minimal model are accurate and reproducible methods. One must remain vigilant regarding limitations of these methods. However, they may be applied with confidence under a wide variety of conditions. Unfortunately it is not possible to recommend simpler (i.e. surrogate) methods that can be applied with confidence. While it might be appropriate to use fasting insulin to reflect insulin resistance in patients without any degree of β‐cell failure, it is usually not possible to determine a priori whether any such defect exists. Thus, one can report fasting insulin simply as a qualitative reflection of insulin resistance. Indices, which also include glucose, appear to add little to the fasting insulin itself. If β‐cell failure progresses, the interpretation of fasting insulin per se becomes impossible. Finally, as of this writing it is not possible to recommend insulin sensitivity measures calculated from the oral glucose tolerance test due to confounds related to differences in gastric emptying, β‐cell function, and glucose effectiveness. Clearly, studies to identify and validate simpler methods to assess insulin action accurately in the intact subject should be continued.

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Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange

Cited by 255 publications

References 20 publications

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis

Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis

Regulation of hepatic metabolism by enteral delivery of nutrients

Measuring Insulin ActionIn Vivo

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