y lipotoxicidad en la diabetes tipo 2
Metabolism 2002 Feb;51(2):163-8
of biotin on glucotoxicity or lipotoxicity in rat pancreatic islets.
Tajiri Y, Sako Y, Hashimoto T, Umeda F, Nawata H.
of Medicine and Bioregulatory Science, Graduated School of Medical
Sciences, Kyushu University, Fukuoka, Japan.
(vitamin H) plays an important role as a cofactor in glucose or lipid
metabolism. We showed that biotin potentiated glucose-induced insulin
release in isolated rat islets, while biotin alone did not affect insulin
release. Coculture with biotin in islets for 48 hours significantly
enhanced glucose-induced insulin release or islet insulin content.
Similarly, preproinsulin or pancreatic/duodenal homeobox-1 (PDX-1) mRNA
was also enhanced in islets cultured with biotin for 48 hours. Furthermore,
we measured effects of biotin on beta-cell function under glucotoxic or
lipotoxic states. In islets cultured with high glucose or palmitate for 48
hours, glucose-induced insulin release or islet insulin content
deteriorated. Coculture with biotin significantly restored glucose-induced
insulin release or islet insulin content together with the restoration of
preproinsulin or PDX-1 mRNA. We conclude that biotin exerts its beneficial
effects on beta-cell dysfunction induced by glucose or free fatty acids
probably through the enhancement of insulin biosíntesis.
Endocrinology 2002 Feb;143(2):339-42
Secondary beta-cell failure in type 2 diabetes--a convergence of
glucotoxicity and lipotoxicity.
V, Robertson RP.
Northwest Research Institute, Seattle, Washington 98122, USA. firstname.lastname@example.org
hyperglycemia and hyperlipidemia can exert deleterious effects on beta-cell
function, respectively referred to as glucotoxicity and lipotoxicity. Over
time, both contribute to the progressive deterioration of glucose
homeostasis characteristic of type 2 diabetes. The mechanisms of
glucotoxicity involve several transcription factors and are, at least in
part, mediated by generation of chronic oxidative stress. Lipotoxicity is
probably mediated by accumulation of a cytosolic signal derived from the
fatty acid esterification pathway. Our view that hyperglycemia is a
prerequisite for lipotoxicity is supported by several recent studies
performed in our laboratories. First, prolonged in vitro exposure of
isolated islets to fatty acids decreases insulin gene expression in the
presence of high glucose concentrations only, and glucose is rate-limiting
for the incorporation of fatty acids into neutral lipids. Second,
normalization of blood glucose in Zucker diabetic fatty rats prevents
accumulation of triglycerides and impairment of insulin gene expression in
islets, whereas normalization of plasma lipid levels is without effect.
Third, high-fat feeding in Goto-Kakizaki rats significantly impairs
glucose-induced insulin secretion in vitro, whereas a similar diet has no
effect in normoglycemic animals. We propose that chronic hyperglycemia,
independent of hyperlipidemia, is toxic for beta-cell function, whereas
chronic hyperlipidemia is deleterious only in the context of concomitant
Rev Med Chil 2001 Jun;129(6):671-9
and lipotoxicity: factors in the pathogenesis and evolution of type 2
diabetes [Article in Spanish]
Garcia de los Rios M. Unidad de Diabetes y Nutricion, Facultad de Medicina
Occidente Universidad de Chile.
toxicity refers to the structural and functional damage in the beta cells
and target tissues of insulin, caused by chronic hyperglycemia. These
alterations cause a lower hormonal secretion and action (insulin
resistance). Lipid toxicity refers to the damage caused by persistently
high free fatty acid levels, as a consequence of triacylglycerol
catabolism. Since elevated glucose and lipid levels cause a similar damage
and interact, the term glucose and lipid toxicity refers to their additive
effects. This toxicity can be implicated in the pathogenesis of type II
diabetes and in the secondary failure of oral hypoglycemic drugs, leading
to the requirement of insulin treatment. Insulin resistance with normal
glucose levels, glucose intolerance and clinical diabetes are the three
recognized stages in the development of type 2 diabetes. Considering that
the first two stages are reversible, a good metabolic control to avoid
glucose and lipid toxicity could revert or avoid the development of
Med 2001 Apr;109(4):55-9, 63-4 [Texto
and glucotoxicity in type 2 diabetes. Effects on development and
of Internal Medicine, Division of Endocrinology and Metabolism, University
of Iowa College of Medicine, Iowa City, USA. email@example.com
fat, excess glucose, or both act on diverse cells and tissues to
counteract insulin-mediated glucose uptake, hepatic regulation of glucose
output, and insulin secretion. These effects are labeled lipotoxicity and
glucotoxicity because, when severe enough, each may contribute to the
diabetic state. Lifestyle modifications and certain new pharmacologic
agents may be effective in modulating these effects and could prove useful
in primary prevention of type 2 diabetes.
Rev Med Liege 1999 Jun;54(6):535-8
and lipotoxicity, two implicated accomplices in the vicious circle of type
2 diabetes. [Article in French]
AJ, Paquot N, Lefebvre PJ.
de Medecine, CHU Sart Tilman, Liege.
2 diabetes mellitus is a dynamic disease whose natural history is
characterized by a progressive aggravation leading to a progressively
severe hyperglycaemia, which generally requires a more complex therapy as
time progresses. Such an evolution results from a vicious circle where
both glucotoxicity and lipotoxicity contribute to reduce insulin secretion
and the action of insulin on cell glucose metabolism. These new concepts
are able to modify the strategies of prevention and treatment of type 2
Clin Geriatr Med 1999 May;15(2):255
AD, Thurman JE.
of Endocrinology, Diabetes, and Metabolism, Department of Internal
Medicine, Saint Louis University School of Medicine, St. Louis, Missouri
concentration of glucose is found within a relatively narrow range of
values for most animal species, yet it has little correlation with maximum
lifespan; however, hyperglycemia in most animals is associated with
premature death. This article presents evidence for hyperglycemia-induced
tissue toxicity and discusses potential mechanisms of glucotoxicity and
implications for the aging organism.
Diabetes 1998 Dec;47(12):1889-93
biochemical properties of glucotoxicity and lipotoxicity in islets
decrease citrate synthase activity and increase phosphofructokinase
YQ, Tornheim K, Leahy JL.
of Endocrinology, Diabetes and Metabolism, University of Vermont,
states are characterized by a raised serum/islet level of triglycerides
and a lowered EC50 (concentration at half-maximal stimulation) for glucose-induced
insulin secretion. Culturing islets with long-chain fatty acids (FAs)
replicates the basal insulin hypersecretion. In a previous study, we
showed that the mechanism involved deinhibition of hexokinase by a 60%
decrease in glucose-6-phosphate (G-6-P). The key event was proposed to be
an increased phosphofructokinase (PFK) Vmax secondary to an upregulatory
effect of the FA metabolite, long-chain acyl-coenzyme A (LC-CoA). We now
show another contributory factor, a lowered content of the PFK inhibitor
citrate. Citrate synthase Vmax and citrate levels were lowered 45% in rat
islets cultured with 250 micromol/l oleate for 24 h. Both effects were
reversed by triacsin C, an inhibitor of fatty acyl-CoA synthetase, the
enzyme that generates LC-CoA. Culturing islets with high doses of glucose
(16.7 mmol/l) for 48 h should also raise cytosolic LC-CoA. As predicted,
citrate synthase Vmax was lowered and PFK Vmax was increased, both in a
triacsin C-reversible fashion. These results show shared selected
functional and biochemical properties in beta-cells of so-called
glucotoxicity and lipotoxicity.