Endocrine Pancreas Plasticity Under Physiological and Pathological Conditions Catherine Bernard-Kargar and Alain Ktorza
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Endocrine Pancreas Plasticity Under Physiological and Pathological Conditions Catherine Bernard-Kargar and Alain Ktorza Endocrine pancreas plasticity may be defined as the of -cell mass in relation to prevailing insulin demand; i.e., the ability of the organ to adapt the -cell mass to the vari- ability of the -cell mass to expand in response to insulin resis- ations in insulin demand. For example, during late tance is altered. pregnancy and obesity, the increase of the -cell mass, We review here the main factors involved in islet plastic-  in association with -cell hyperactivity, contributes to ity in adults and the possible causes of its deterioration in insulin oversecretion in response to insulin resistance. type 2 diabetes. There is increasing evidence that the ability of the  -cell mass to expand in adult mammals is much higher  than previously thought. During pregnancy, placental FACTORS INVOLVED IN -CELL MASS CHANGES hormones, especially placental lactogens, are mainly IN THE ADULT responsible for the changes in -cell mass. The factors During development, endocrine cells arise from undifferen- involved in -cell growth in obesity are far from clear, tiated stem cells located in pancreatic ducts, which migrate although increased free fatty acids seem to be the main into the exocrine pancreas to form the islets of Langerhans candidate. Many data suggest that the impairment of (neogenesis). Then, differentiated -cells proliferate within insulin secretion in type 2 diabetes is partly related to the islets (replication). These processes are essential during  reduction of -cell mass, at least relative to prevailing development of the endocrine pancreas, but they are also nec- insulin demand. This defect may originate from genetic essary for the further islet cell mass homeostasis. predisposition, but the situation is likely worsened by  environmental factors such as hyperglycemia (gluco- In vitro and in vivo studies have shown that -cells from toxicity) and hyperlipidemia (lipotoxicity). Better fetuses and adults respond to the same stimuli: nutrients, understanding of -cell growth and regeneration mech- hormones, or growth factors. In this review, we will focus only anisms may allow new strategies in the treatment of on the role of glucose and insulin. type 2 diabetes based on early limitation of -cell dam- Glucose appears to be a potent stimulus of pancreatic age and/or restoration of a functional -cell mass. Dia- -cell growth both in vitro and in vivo. In vitro, the prolifer- betes 50 (Suppl. 1):S30–S35, 2001 ative rate of rodent -cells increases with increasing glucose concentrations (1). The proliferative response of human islets to glucose is also important but is already maximal at low glucose concentrations (5.6 mmol/l) (2). ndocrine pancreas plasticity may be defined as the In adult humans and rats, the -cell mass seems quite sta- ability of the organ to adapt the -cell mass to the ble with a low -cell replication rate (3% per day vs. 10% per variations in insulin demand to warrant optimal day in the fetus) (3). For this reason, the role of glucose in control of glucose homeostasis. Our current adult islets was considered marginal. However, the potent E   knowledge is that in adult mammals, the -cell mass is gov- effect of glucose on -cell mass growth was clearly demon- erned by a permanent balance between -cell growth (-cell strated by Bonner-Weir et al. (4) in nondiabetic rats infused replication and neogenesis) and -cell death (mainly apo- with glucose for 96 h. This effect resulted from both -cell ptosis). Disruption of this balance may lead to rapid and hyperplasia and hypertrophy. Using a similar protocol of marked changes in islet cell mass. For example, during late glucose infusion in unrestrained rats, we further stressed the pregnancy and obesity, the increase of the -cell mass con- impressive efficiency of glucose on -cell growth because a tributes to insulin oversecretion in response to insulin resis- 24-h glucose infusion was sufficient to maximally increase the tance. There is now growing evidence that impaired insulin -cell mass in both nondiabetic and mildly diabetic rats (5) secretion in type 2 diabetes is in part related to the reduction (Fig. 1). The potent and rapid effect of glucose infusion was even more impressive in mildly diabetic rats because glucose promoted complete regeneration of -cell mass (mild dia- From the Laboratoire de Physiopathologie de la Nutrition, Université Paris, Paris, France. betes was induced by low-dose streptozotocin, resulting in Address correspondence and reprint requests to Alain Ktorza, Labora- a 50% reduction of -cell mass). The increase of -cell mass toire de Physiopathologie de la Nutrition, CNRS ESA 7059, Université was due mainly to rapid activation of neogenesis of new Paris 7, Tour 23-33, 1° étage, case 7126, 2 Place Jussieu, 75251 Paris cedex  05, France. E-mail: [email protected]. endocrine cells rather than to increase in -cell proliferation Received for publication 21 May 2000 and accepted 28 August 2000. (5) (Figs. 2–4). A role for glucose in -cell regeneration was This article is based on a presentation at a symposium. The symposium indirectly suggested by previous studies showing that the and the publication of this article were made possible by an unrestricted reduction of -cell mass induced by a high dose of strepto- educational grant from Les Laboratoires Servier. FFA, free fatty acid; IRS, insulin receptor substrate; MODY, maturity- zotocin in the neonate rat (6), 90% pancreatectomy in young onset diabetes of the young. adult rats (7), or cellophane wrapping of the head of the S30 DIABETES, VOL. 50, SUPPLEMENT 1, FEBRUARY 2001 C. BERNARD-KARGAR AND A. KTORZA pancreas in hamsters (8) was followed by sustained -cell regeneration (50–75% of control). In all the above studies, par- tial restoration of the -cell mass did not prevent hypergly- cemia; therefore, it was inferred that the increase in -cell mass was favored by high glucose levels (3). In addition to promoting -cell neogenesis and/or replication, glucose may be involved in the control of apoptosis by inhibition of the -cell “suicide” program (9). In short-term exposure to glu- cose, it seems that the -cell apoptotic rate decreases and the number of viable -cells increases when glucose concen- tration is raised (9). Nevertheless, the precise role of changes in glucose con- centration is difficult to appreciate in vivo because of the inter- ference of concomitant variations in plasma insulin levels. Interplay between glucose and insulin seems to be important for the control of islet cell proliferation in vivo (10). Moreover, some studies have shown that insulin itself may stimulate pan- creatic cell mitosis in vitro (11). In vivo studies also suggest that insulin may be involved in -cell growth. Indeed, insulin treatment stimulates -cell proliferation in fetal islets trans- planted into diabetic rats (12,13). Moreover, insulin therapy improved -cell regeneration in newborn rats injected with FIG. 1. Total pancreatic -cell mass variations in nondiabetic (ᮀ) and diabetic () rats infused with glucose for 48 h. Values are streptozotocin on the day of birth (14). It must be pointed out means ± SE of three to five rats in each group. *P < 0.05. that in experiments showing the promoting effect of insulin FIG. 2. Evidence of endocrine cell budding from pancreatic ducts in the pancreas of rats infused with glucose for 24 h. Endocrine cells were immunostained for insulin (A), glucagon (B), somatostatin (C), and pancreatic polypeptide (D) and revealed with peroxidase. Magnifica- .tion ؋400 DIABETES, VOL. 50, SUPPLEMENT 1, FEBRUARY 2001 S31 ISLET PLASTICITY FIG. 4. -Cell replication rates expressed as the percentage of -5-bromo-2deoxyuridine (BrdU)-positive -cells per 6 h in nondia betic (ᮀ) and diabetic () rats infused with glucose for 48 h. Values are means ± SE of three to five rats in each group. *P < 0.05. adult rats. However, this does not exclude long-term effects of insulin and/or the fact that both hyperglycemia and hyper- insulinemia are required for maximal islet growth. The inter- est in the role of insulin was highlighted by recent studies showing that endocrine pancreas plasticity was tightly dependent on the islet insulin receptor, insulin receptor sub- strate (IRS)-1 and IRS-2. In mice, knockout of IRS-1 pro- vokes insulin resistance compensated by increased -cell mass (17). On the other hand, mice deficient for IRS-2 rapidly FIG. 3. Evidence of insulin-positive cell budding from pancreatic developed diabetes after birth because of the reduction of ducts in the pancreas of rats infused with glucose for 24 h. A: -Cell   cluster near a pancreatic duct to which it is attached by collagen -cell mass and altered -cell function (18). Four-month-old fibers (magnification ؋200). B: Presence of -cells within the duc- knockout mice for the insulin receptor presented altered tal epithelium (magnification ؋1,000). In brown: insulin-positive insulin secretion in response to glucose and decreased -cell cells revealed with peroxidase. In blue: collagen fibers revealed with mass (19). However, according to recent data, the role played aniline blue. by IRS-2 in endocrine pancreas plasticity could depend on IGF-I receptor activation (20). Thus, it is possible that the treatment on -cell regeneration, plasma glucose remained effect of insulin on -cell growth could in fact be due to IGF- higher than normal (12,13). The need for a critical plasma glu- I. In any case, the pancreatic response to variations of the cose level for -cell growth was further emphasized by the insulin demand seems to involve the key role of IRS-2. study of Koiter et al. (10), who observed that hyperinsuline- mia associated with hypoglycemia suppressed -cell repli- ENDOCRINE PANCREAS PLASTICITY IN NONDIABETIC cation in rats. Taken together, these studies stress the diffi- SUBJECTS culty in appreciating the specific role of insulin in vivo on the Pregnancy.