Download Pancréas et cellules bêta

Stéphanie Migrenne (France)
Pancreas and beta cells
Focus on C. Wollheims’ lecture
during SFD meeting (Geneva, 22-25 March 2011):
“The Langerhans islet at the heart of Diabetes”
Key role of Langerhans islets in pathophysiology of type 2 diabetes (T2D) has been
highlighted in different models. Indeed, as well described, T2D is a common disease caused
by both impaired insulin action (insulin resistance) and insulin secretion and growing amount
of data evidenced that loss of beta cell mass is one of the main factors involved in decreased
insulin secretion. Physiologically, the first step of glucose induced insulin secretion (GIIS) is
its conversion into pyruvate through the glycolysis pathway in the cytosol of the beta cell.
Pyruvate is then transferred to the mitochondria where it induces the generation of NADH and
FADH2 in the tricarboxylic acid cycle. Oxidation of these reduced equivalents drives proton
pumping of respiratory chain complexes, resulting in hyperpolarization of the electrical
potential and mitochondrial matrix alkalinisation. Such changes enhance mitochondrial ATP
synthesis. Increasing ATP production induce closure of ATP-sensitive K+ channels located in
plasma membrane, causing depolarization, opening of voltage dependent Ca2+ channels and
finally increased cytosolic free Ca2+ concentration which leads to insulin exocytosis. The rise
in cytosolic Ca2+ is relayed into the mitochondria, where ions potentiate oxidative
metabolism. Islets obtained after autopsy from type 2 diabetic patients have altered
mitochondrial morphology, impaired glucose oxidation and reduced ATP generation,
explaining defective insulin secretion. The maturity-onset diabetes of the young 4 (MODY4)
which is associated to heterozygosis of the pancreatic homeodomain transcription factor Pdx1
(pancreatic duodenal homeobox 1) is characterized by blunted GIIS linked to impaired
mitochondrial function, a consequence of decreased transcription of mitochondrial (mt)DNAencoded enzyme subunits of the respiratory chain. It has been recently proposed that Pdx1
may regulate transcription of mtDNA-encoded genes via regulation of the mitochondrial
transcription factor A (TFAM), a nuclear-encoded factor which controls stability and
transcriptional activity of mtDNA. Thus, the genetic control by the beta-cell-specific factor
Pdx1 of the ubiquitous gene TFAM maintains beta-cell mtDNA vital for ATP production and
normal GIIS. Screening of TFAM genetic variants might be warranted in type 2 diabetic
patients with impaired insulin secretion.
In type I diabetes, islets are virtually devoid of beta-cells, and are largely made up of
hyperplastic alpha-cells, and -without the inhibitory action of insulin- their secretion of
glucagon is unrestrained, and glucagon action on the liver is unopposed. Interestingly, in
glucagon receptor-null (Gcgr-/-) mice treated with streptozotocin to achieve complete insulin
deficiency, none of the clinical or laboratory manifestations of diabetes appeared. Moreover,
fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal, even
though no rise in insulin was detected in peripheral plasma. This suggests that in mice type 1
diabetes can be converted into an asymptomatic, benign, noncatabolic, insulin-independent
disorder by elimination of glucagon action. These studies support the clinical utility of the
development of potent Gcgr antagonists and/ or glucagon suppressors capable of eliminating
the lethal glucagon-dependent component of type 1 diabetes.