Stéphanie Migrenne (France)
Pancreas and beta cells
Focus on C. Wollheims’ lecture
duringSFD 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 betacell 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 FADH2in 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 induceclosure of ATP-sensitive K+ channels located inplasma membrane, causingdepolarization, opening of voltage dependentCa2+channels and finally increased cytosolicfree 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 homeobox1) is characterized by blunted GIIS linked to impaired mitochondrial function, a consequenceof decreased transcription of mitochondrial (mt)DNA-encoded enzymesubunits of the respiratory chain. It has been recently proposed that Pdx1 mayregulate 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, thegenetic control by the beta-cell-specific factor Pdx1 ofthe ubiquitous gene TFAM maintains beta-cell mtDNAvital 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 devoidof beta-cells, and are largely made up of hyperplastic alpha-cells, and -withoutthe 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 diabetesappeared. Moreover, fasting glucose levels and oral and intraperitonealglucose tolerance tests were normal,even though no rise in insulin wasdetected in peripheral plasma. This suggests thatin mice type1 diabetes can be converted into an asymptomatic, benign,noncatabolic, insulin-independent disorder by eliminationof glucagon action. These studies support the clinicalutility of the development of potent Gcgr antagonists and/or glucagon suppressors capable of eliminating the lethalglucagon-dependent component of type 1 diabetes.