Pancreatic steatosis in humans: cause or marker of lipotoxicity?
OBJECTIVE
Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion. Chronically increased levels of plasma nonesterified fatty acids (NEFA) and triglyceride-rich lipoproteins impair beta-cell function, a process referred to as lipotoxicity. Furthermore, when NEFA supply exceeds metabolic capacity, lipids accumulate in nonadipose tissues, such as pancreatic islets, inducing organ dysfunction. The purpose of this review is to describe the mechanisms underlying lipotoxicity in vitro, to discuss the evidence for lipotoxicity in vivo and to address whether pancreatic lipid accumulation interferes with insulin secretion in humans.


RESULTS
Although numerous in-vitro studies have shown that chronically elevated NEFA levels induce beta-cell dysfunction and apoptosis, studies in humans are less conclusive. It has been acknowledged that concurrent hyperglycaemia amplifies the adverse effects of elevated plasma NEFA levels on beta-cell function; therefore glucolipotoxicity should be the preferred term. Lipid accumulation in pancreatic islets impaired beta-cell secretory capacity in leptin-deficient rodents. In humans, recent studies employing noninvasive magnetic resonance-technology and computed tomography-technology, lipid accumulation in the pancreas was increased in individuals with impaired glucose metabolism and T2DM. However, there was no clear association with beta-cell dysfunction.


CONCLUSIONS
To date, it is difficult to provide evidence that intraislet lipid accumulation truly exists in humans and that it is indeed causal to beta-cell dysfunction. Additional research is warranted to further detail the nature and role of pancreatic lipid content in humans, its consequence for the postulated processes pertinent to glucolipotoxicity and its contribution to the progressive nature of beta-cell dysfunction in prediabetes.
van Raalte
Daniël H
DH
Diabetes Centre, Department of Internal Medicine, VU University Medical Centre, Amsterdam, The Netherlands. d.vanraalte@vumc.nl
van der Zijl
Nynke J
NJ
Diamant
Michaela
M
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000172:deficiency; D052439:Lipid Metabolism Disorders / Q000150:complications / Q000503:physiopathology*; D010179:Pancreas / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000150:complications / Q000378:metabolism*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin