Mechanisms modifying glucose oxidation in diabetes mellitus

Randle, P. J.; Priestman, David A.; Mistry, Sharad; Halsall, A.

doi:10.1007/bf00400839

Cited by 155 publications

(116 citation statements)

References 48 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…This is in agreement with their insulin resistance, because NEFA have an inhibitory effect on many key enzymes in glucose metabolism [26]. Lipid oxidation consists of oxidation of intracellular lipids and blood-borne fatty acids [27].…”

Section: Discussionsupporting

confidence: 66%

Intramuscular triglyceride content is increased in IDDM

et al. 1998

View full text Add to dashboard Cite

Increased lipid oxidation is related to insulin resistance [1]. Most of the fatty acids taken up by resting muscle are not oxidized directly, but enter an intramuscular pool with a slow turnover at rest and are the immediate source of lipid substrate for oxidation [2]. The NEFA taken up by muscle are incorporated to lipid droplets in muscle and 70--90 % of fatty acids entering the muscle are rapidly esterified to triglyceride (TG) [3]. For example, raising extracellular palmitate increases esterification, but does not increase intramuscular concentration of palmitate [4]. Part of the enhanced lipid oxidation can be derived from intramuscular sources [5].As compared to healthy subjects a sixfold increase of muscle (m) TG in patients with non-insulin-dependent diabetes mellitus [6], and a sevenfold increase in TG content in striated muscle in coronary bypass-operated patients with impaired glucose tolerance [7] have been reported in comparison to control groups. These patient groups are also characterized by insulin resistance. Sustained euglycaemic hyperinsulinaemia Diabetologia (1998) Summary Increased lipid oxidation is related to insulin resistance. Some of the enhanced lipid utilization may be derived from intramuscular sources. We studied muscle triglyceride (mTG) concentration and its relationship to insulin sensitivity in 10 healthy men (age 29 ± 2 years, BMI 23.3 ± 0.6 kg/m 2 ) and 17 men with insulin-dependent diabetes mellitus (IDDM) (age 30 ± 2 years, BMI 22.8 ± 0.5 kg/m 2 , diabetes duration 14 ± 2 years, HbA 1 c 7.7 ± 0.3 %, insulin dose 48 ± 3 U/day). Insulin sensitivity was measured with a 4 h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol ⋅ kg --1 ⋅ min --1 ) clamp accompanied by indirect calorimetry before and at the end of the insulin infusion. A percutaneous biopsy was performed from m. vastus lateralis for the determination of mTG. At baseline the IDDM patients had higher glucose (10.2 ± 0.9 vs 5.6 ± 0.1 mmol/l, p < 0.001), insulin (40.3 ± 3.2 vs 23.2 ± 4.2 pmol/l, p < 0.01), HDL cholesterol (1.28 ± 0.06 vs 1.04 ± 0.03 mmol/l, p < 0.01) and mTG (32.9 ± 4.6 vs 13.6 ± 2.7 mmol/kg dry weight, p < 0.01) concentrations than the healthy men, respectively. The IDDM patients had lower insulin stimulated whole body total (--25 %, p < 0.001), oxidative (--18 %, p < 0.01) and non-oxidative glucose disposal rates (--43 %, p < 0.001), whereas lipid oxidation rate was higher in the basal state ( + 44 %, p < 0.01) and during hyperinsulinaemia ( + 283 %, p < 0.05). mTG concentrations did not change significantly during the clamp or correlate with insulin stimulated glucose disposal. In healthy men mTG correlated positively with lipid oxidation rate at the end of hyperinsulinaemia (r = 0.75, p < 0.05). In conclusion: 1) IDDM is associated with increased intramuscular TG content. 2) mTG content does not correlate with insulin sensitivity in healthy subjects or patients with IDDM. [Diabetologia (1998) 41: 111--115]

show abstract

Section: Discussionsupporting

confidence: 66%

Intramuscular triglyceride content is increased in IDDM

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Studies in pancreatic islets show that palmitate increases cytosolic Ca 2þ in a fuel-dependent mechanism (Warnotte et al, 1997). However, the long-term exposure (6-24 h) to high FFA concentration can inhibit insulin secretion, possibly via glucose-fatty acid cycle as originally proposed by Randle et al (1994). Rat and human islets exposed to FA for 48 h show increased insulin release at basal glucose concentration (3 mM) and decreased release when glucose concentration is high (27 mM) (Zhou and Grill, 1995).…”

Section: Plasma Fa and Insulin Secretionmentioning

confidence: 94%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

149

View full text Add to dashboard Cite

Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic b-cells have long been recognized. Acute exposure of the pancreatic b-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for b-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acylCoA (LC-CoA) controls several aspects of the b-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide-and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.

show abstract

“…The heart depends on fatty acid oxidation for a large proportion ( 70%) of its energy requirements, even under normoinsulinaemic conditions. In hypoinsulinaemic or insulin-resistant states this proportion is even higher, owing primarily to the chronic inhibition of PDH [73]. The latter is achieved acutely through the generation of mitochondrial acetyl-CoA as a product of fatty acid oxidation, and chronically through the fatty acid-mediated increase in the expression of PDH kinase [74,75].…”

Section: Cardiac Musclementioning

confidence: 99%

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit

1999

Biochemical Journal

View full text Add to dashboard Cite

Long-chain acyl-CoA esters have potent specific actions (e.g. on gene transcription, membrane trafficking) as well as non-specific ones (e.g. on phospholipid bilayers). They are synthesized on the cytosolic aspects of several intracellular membranes, to give rise to (a) cytosolic pool(s) to which a variety of enzymes and processes have access, including some localized in the nucleus. Their concentration in cells is highly regulated, interconversion with corresponding acylcarnitines being the most important mechanism involved. This reaction is catalysed by cytosol-accessible carnitine long-chain acyl (palmitoyl) transferase activities that are themselves located on multiple membrane systems. Regulation of these activities is through the inhibitory action of malonyl-CoA. Hence the existence of a potent malonyl-CoA-acyl-CoA axis through which many processes involved in the maintenance of mammalian cell function are regulated. The molecular, topographical and physiological interactions that make this possible are described and discussed.

show abstract

Mechanisms modifying glucose oxidation in diabetes mellitus

Cited by 155 publications

References 48 publications

Intramuscular triglyceride content is increased in IDDM

Intramuscular triglyceride content is increased in IDDM

Pleiotropic effects of fatty acids on pancreatic β‐cells

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Contact Info

Product

Resources

About