Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose

Bock, Gerlies; Chittilapilly, Elizabeth; Basu, Rita; Toffolo, Gianna; Cobelli, Claudio; Chandramouli, Visvanathan; Landau, Bernard R.; Rizza, Robert A.

doi:10.2337/db06-1776

Cited by 128 publications

(116 citation statements)

References 55 publications

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“…In the latter study, postprandial insulin sensitivity was reduced and peripheral insulin sensitivity tended to be reduced in IGT as compared with IFG subjects. This is in line with previous studies showing impaired hepatic and peripheral IR as primary disorders in IFG and IGT subjects, respectively (5)(6)(7) , indicating that the development of IR may be tissue-specific and that IFG and/or IGT may represent distinct pathways towards T2DM.…”

Section: Skeletal Muscle Lipid Uptakesupporting

confidence: 92%

“…IFG (fasting glucose >5·6 mM/l) and IGT (2 h oral glucose tolerance testderived glucose concentration >7·8 mM) are intermediate states in the transition from a normal glucose tolerance towards T2DM. IFG and IGT may represent distinct pathways towards T2DM, with impaired hepatic and peripheral insulin sensitivity as the predominant disorders in IFG and IGT subjects, respectively (5)(6)(7) . Recently, a dualstable-isotope tracer approach was validated to study FA partitioning, the metabolic fate of dietary compared with Corresponding author: Prof E. E. Blaak, email e.blaak@maastrichtuniversity.nl Abbreviations: DAG, diacylglycerol; E%, % of energy expenditure; FA, fatty acid; FSR, fractional synthetic rate; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IR, insulin resistance; LPL, lipoprotein lipase; T2DM, type 2 diabetes mellitus.…”

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confidence: 99%

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Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes

Blaak

2017

Proc. Nutr. Soc.

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The obese insulin resistant and/or prediabetic state is characterised by systemic lipid overflow, mainly driven by an impaired lipid buffering capacity of adipose tissue, and an impaired capacity of skeletal muscle to increase fat oxidation upon increased supply. This leads to the accumulation of bioactive lipid metabolites in skeletal muscle interfering with insulin sensitivity via various mechanisms. In this review, the contribution of dietary v. endogenous fatty acids to lipid overflow, their extraction or uptake by skeletal muscle as well as the fractional synthetic rate, content and composition of the muscle lipid pools is discussed in relation to the development or presence of insulin resistance and/or an impaired glucose metabolism. These parameters are studied in vivo in man by combining a dual stable isotope methodology with [ 2 H 2 ]-and [U-13 C]-palmitate tracers with the arterio-venous balance technique across forearm muscle and biochemical analyses in muscle biopsies. The insulin-resistant state is characterised by an elevated muscle TAG extraction, despite similar supply, and a reduced skeletal muscle lipid turnover, in particular after intake of a high fat, SFA fat meal, but not after a high fat, PUFA meal. Data are placed in the context of current literature, and underlying mechanisms and implications for long-term nutritional interventions are discussed. The prevalence of overweight and overweight-related metabolic disturbances is increasing at an alarming rate. Worldwide more than 50 % of the adults is overweight (>one billion individuals) and a further 12 % (475 million) can be classified as clinically obese. Every year at least 2·8 million adults die as a result of being overweight/obese (http://www.who.int/gho/ncd/risk_fac-tors/overweight/en). Obesity is an important risk factor for chronic metabolic diseases such as type 2 diabetes mellitus (T2DM) and CVD. A disturbed lipid metabolism in multiple tissues, including adipose tissue, liver, skeletal muscle, gut and pancreas may play an important role in the development of insulin resistance (IR), an impaired glucose metabolism and T2DM. These disturbances, in particular an impaired adipose tissue lipid handling, may lead to systemic lipid overflow, increased circulating concentrations of NEFA and TAG and accumulation of lipids in non-adipose tissues (1)(2)(3)(4) . This lipid overflow together with an impaired capacity to adjust fatty acid (FA) oxidation to FA supply in skeletal muscle (metabolic inflexibility (3) ) may cause excess fat storage in skeletal muscle, which is related to the development or worsening of IR. IR in concert with progressive β-cell failure leads to an increased blood glucose concentration in the non-diabetic range, classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). IFG (fasting glucose >5·6 mM/l) and IGT (2 h oral glucose tolerance testderived glucose concentration >7·8 mM) are intermediate states in the transition from a normal glucose tolerance towards T2DM. IFG and IGT may represent dis...

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Section: Skeletal Muscle Lipid Uptakesupporting

confidence: 92%

mentioning

confidence: 99%

Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes

Blaak

2017

Proc. Nutr. Soc.

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“…Thus, chronic overproduction of glucose causing glucose toxicity-induced insulin resistance and impaired insulin secretion are factors which are ultimately responsible for the development of glucose intolerance in this model. Furthermore, our data support the recent clinical findings from Bock et al (2007), who demonstrated that impaired insulin secretion and extrahepatic insulin resistance are the primary causes of postprandial hyperglycaemia in patients with increased GNG.…”

Section: Discussionsupporting

confidence: 81%

A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

Mangiafico

Lim²,

Neoh³

et al. 2011

Journal of Endocrinology

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Increased glucose production is associated with fasting hyperglycaemia in type 2 diabetes but whether or not it causes glucose intolerance is unclear. This study sought to determine whether a primary defect in gluconeogenesis (GNG) resulting in elevated glucose production is sufficient to induce glucose intolerance in the absence of insulin resistance and impaired insulin secretion. Progression of glucose intolerance was assessed in phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats, a genetic model with a primary increase in GNG. Young (4-5 weeks of age) and adult (12-14 weeks of age) PEPCK transgenic and Piebald Virol Glaxo (PVG/c) control rats were studied. GNG, insulin sensitivity, insulin secretion and glucose tolerance were assessed by intraperitoneal and intravascular substrate tolerance tests and hyperinsulinaemic/euglycaemic clamps. Despite elevated GNG and increased glucose appearance, PEPCK transgenic rats displayed normal glucose tolerance due to adequate glucose disposal and robust glucose-mediated insulin secretion. Glucose intolerance only became apparent in the PEPCK transgenic rats following the development of insulin resistance (both hepatic and peripheral) and defective glucose-mediated insulin secretion. Taken together, a single genetic defect in GNG leading to increased glucose production does not adversely affect glucose tolerance. Insulin resistance and impaired glucose-mediated insulin secretion are required to precipitate glucose intolerance in a setting of chronic glucose oversupply.

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“…In the muscle, both glucose and FFA are used to convert P into ATP, with rates that depend on P IGm and P Am respectively, as described by equations (10), (11) and (13). These two fluxes are plotted in the lower left and lower centre plots in Figure 10.…”

Section: Graphs Of Fluxesmentioning

confidence: 99%

“…Similarly, with non-diabetic obese subjects there is reduced hepatic glucose output suppression from insulin [3,5] and reduced skeletal muscle glucose uptake [9]. It has also been shown that insulin resistant subjects can have increased hepatic lipogenesis, resulting in larger changes in hepatic triglyceride concentrations in the post prandial state which is counter intuitive as it is an insulin stimulated pathway; however, it was also shown that the insulin resistant subjects had a much greater reduction in muscle glucose uptake indicating that insulin resistance affects different tissues to different degrees [10] with the liver being less severely affected [11]. It is not just glucose metabolism that is affected by insulin resistance, it also affects adipose tissue with reduced insulin suppression of free fatty acid release common in obesity [9].…”

Section: Introductionmentioning

confidence: 99%

A Mathematical Model of the Human Metabolic System and Metabolic Flexibility

et al. 2014

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. Abstract In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the post prandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin, and insulin-resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility.In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare.

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Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose

Cited by 128 publications

References 55 publications

Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes

Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes

A primary defect in glucose production alone cannot induce glucose intolerance without defects in insulin secretion

A Mathematical Model of the Human Metabolic System and Metabolic Flexibility

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