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Elucidating the mechanisms by which pancreatic β-cells couple glucose sensing to insulin secretion, a vital process in energy homeostasis, is of prime importance. Although ATP production is considered the main [...], OBJECTIVE--Insulin secretion involves complex events in which the mitochondria play a pivotal role in the generation of signals that couple glucose detection to insulin secretion. Studies on the mitochondrial generation of reactive oxygen species (ROS) generally focus on chronic nutrient exposure. Here, we investigate whether transient mitochondrial ROS production linked to glucose-induced increased respiration might act as a signal for monitoring insulin secretion. RESEARCH DESIGN AND METHODS--ROS production in response to glucose was investigated in freshly isolated rat islets. ROS effects were studied using a pharmacological approach and calcium imaging. RESULTS--Transient glucose increase from 5.5 to 16.7 mmol/l stimulated ROS generation, which was reversed by antioxidants. Insulin secretion was dose dependently blunted by antioxidants and highly correlated with ROS levels. The incapacity of β-cells to secrete insulin in response to glucose with antioxidants was associated with a decrease in ROS production and in contrast to the maintenance of high levels of ATP and NADH. Then, we investigated the mitochondrial origin of ROS (mROS) as the triggering signal. Insulin release was mimicked by the mitochondrial-complex blockers, antimycin and rotenone, that generate mROS. The adding of antioxidants to mitochondrial blockers or to glucose was used to lower mROS reversed insulin secretion. Finally, calcium imaging on perifused islets using glucose stimulation or mitochondrial blockers revealed that calcium mobilization was completely reversed using the antioxidant trolox and that it was of extracellular origin. No toxic effects were present using these pharmacological approaches. CONCLUSIONS--Altogether, these complementary results demonstrate that mROS production is a necessary stimulus for glucose-induced insulin secretion.

FATTY ACIDS AND NERVOUS CONTROL OF ENERGY HOMEOSTASIS It is now well established that fatty acids (FAs) act on the central nervous system as important physiological regulators of glucose metabolism [...], It is now clearly demonstrated that fatty acids (FAs) may modulate neural control of energy homeostasis and specifically affect both insulin secretion and action. Indeed, pancreatic β-cells receive rich neural innervation and FAs induce important changes in autonomic nervous activity. We previously reported that chronic infusion of lipids decreased sympathetic nervous system activity and led to exaggerated gincose-induced insulin secretion (GIIS), as would be expected from the known inhibitory effect of sympathetic splanchnic nerve activity on insulin secretion. Intracarotid infusion of lipids that do not change plasma FA concentrations also lead to increased GIIS. This effect of FAs on GIIS was prevented by inhibition of β-oxidation. It is noteworthy that a single intracarotid injection of oleic acid also induced a transient increase in plasma insulin without any change in plasma glucose, suggesting that FAs per se can regulate neural control of insulin secretion. Finally, using whole cell current clamp recordings in hypothalamic slices and calcium imaging in dissociated hypothalamic neurons, we identified a hypothalamic subpopulation of neurons either excited (13%) or inhibited (6%) by FAs. Thus, FAs per se or their metabolites modulate neuronal activity, as a means of directly monitoring ongoing fuel availability by central nervous system nutrient-sensing neurons involved in the regulation of insulin secretion.

Elucidating the signaling mechanisms by which cells sense nutrient or metabolic status, a vital process in energy homeostasis, is of prime importance. Glucose-sensing mechanisms have been mainly characterized in two [...], The physiological signaling mechanisms that link glucose sensing to the electrical activity in metabolism-regulating hypothalamus are still controversial. Although ATP production was considered the main metabolic signal, recent studies show that the glucose-stimulated signaling in neurons is not totally dependent on this production. Here, we examined whether mitochondrial reactive oxygen species (mROS), which are physiologically generated depending on glucose metabolism, may act as physiological sensors to monitor the glucose-sensing response. Transient increase from 5 to 20 mmol/l glucose stimulates reactive oxygen species (ROS) generation on hypothalamic slices ex vivo, which is reversed by adding antioxidants, suggesting that hypothalamic cells generate ROS to rapidly increase glucose level. Furthermore, in vivo, data demonstrate that both the glucose-induced increased neuronal activity in arcuate nucleus and the subsequent nervous-mediated insulin release might be mimicked by the mitochondrial complex blockers antimycin and rotenone, which generate mROS. Adding antioxidants such as trolox and catalase or the uncoupler carbonyl cyanide m-chlorophenylhydrazone in order to lower mROS during glucose stimulation completely reverses both parameters. In conclusion, the results presented here clearly show that the brain glucose-sensing mechanism involved mROS signaling. We propose that this mROS production plays a key role in brain metabolic signaling.

NUTRITION-INDUCED DIABETES IN PSAMMOMYS OBESUS Psammomys obesus is a diurnal gerbil that lives in North African and Eastern Mediterranean semi-desert regions. The Israeli P. obesus colony was established at the [...], Type 2 diabetes is characterized by insulin resistance and progressive β-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate β-cell function and/or reduced β-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of β-cell dysfunction versus decreased β-cell mass to the 'β-cell failure' of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and β-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in β-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans.

Pancreatic insulin reserve is an important parameter of islet function, with tight coupling between insulin secretion and production being necessary for the adequate functioning of the β-cell (rev. in 1). [...], Recent studies ascribe a major role to pancreatic β-cell loss in type 2 diabetes. We investigated the dynamics of β-cell mass during diabetes evolution in Psammomys obesus, a model for nutrition-dependent type 2 diabetes, focusing on the very early and the advanced stages of the disease. P. obesus fed a high-calorie diet for 26 days developed severe hyperglycemia, β-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring β-cell granulation and insulin content. To dissociate effects of diet from blood glucose reduction, diabetic animals received phlorizin for 2 days, which normalized glycemia and increased the pancreatic insulin reserve to 50% of control, despite a calorie-rich diet. During diabetes progression, β-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, β-cell mass did not correlate with degree of hyperglycemia or pancreatic insulin content. We conclude that reduced insulin reserve is the main cause of diabetes progression, whereas irreversible β-cell mass reduction is a late event in P. obesus. The rapid recovery of the pancreas by phlorizin-induced normoglycemia implies a causal relationship between hyperglycemia and islet dysfunction. Similar mechanisms could be operative during the evolution of type 2 diabetes in humans.

We investigated the effect of glucose infusion on Β-cell regeneration in rats made mildly diabetic by a single injection of low dosage (35 mg/kg) streptozotocin (STZ). Nondiabetic (ND) and STZ [...]

A New Tool for the Identification and Sorting of Β-Cell Subpopulations With Different Functional Activity To clarify the relationship between variations in Β-cell mass and pancreatic function, we investigated the [...]

Endocrine pancreas plasticity may be defined as the ability of the organ to adapt the Β-cell mass to the variations in insulin demand. For example, during late pregnancy and obesity, [...]

Impaired insulin secretion is an important component of non-insul independent diabetes (NIDDM). Its origin is not clear but there is increasing evidence of the existence of an inadequate Β-cell mass [...]

Plasma metabolite concentrations reflect the activity of tissue metabolic pathways and their quantitative determination may be informative about pathogenic conditions. We searched for plasma lipid species whose concentrations correlate with various parameters of glucose homeostasis and susceptibility to type 2 diabetes (T2D). Shotgun lipidomic analysis of the plasma of mice from different genetic backgrounds, which develop a pre-diabetic state at different rates when metabolically stressed, led to the identification of a group of sphingolipids correlated with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in the plasma of individuals from two population-based prospective cohorts revealed that specific long-chain fatty-acid-containing dihydroceramides were significantly elevated in the plasma of individuals who will progress to diabetes up to 9 years before disease onset. These lipids may serve as early biomarkers of, and help identify, metabolic deregulation in the pathogenesis of T2D.

Gil Leibowitz, (1) Gokhan Uckaya, (1) Philippe Delagrange, (2) Alain Chavanieu, (3) Gerard Grassy, (3) Marie-France Berthault, (4) Alain Ktorza, (4,5) Erol Cerasi, (1) Nurit Kaiser (1) From the (1) [...], Glucagon-like peptide (GLP)-1 analogs are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analog, S 23521 [([a.sup.8]-des [R.sup..36]) GLP-1-(7-37)-NH], on the progression of diabetes in the Psammomys obesus model of type 2 diabetes. Animals with marked hyperglycemia were given twice-daily injections of 100 µg/kg S 23521 for 15 days. Food intake was decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycemia was noted in controls, as opposed to maintenance of pretreatment glucose levels in the S 23521 group. Treated animals had higher serum insulin, insulinogenic index, and leptin, whereas plasma triglyceride and FFA levels were decreased. S 23521 induced a fivefold increase in pancreatic insulin content. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; β-cell apoptosis was ~70% reduced, without change in β-cell proliferation, resulting in a twofold increase in relative β-cell volume. Thus, S 23521 prevented the progression of diabetes in Psammomys obesus with marked improvement of the metabolic profile, pancreatic insulin reserve, and β-cell mass. These effects emphasize the feasibility of preventing metabolic deterioration over time in type 2 diabetes.

A novel series of dual PPAR/ agonists was designed through the modification of our previously described family of 8-HETE analogs. The combination of the structural elements of this family and of the classical PPAR ligands produced compounds with a quinoxaline core and two sides chains. Structure-activity relationship studies have been carried out on the new series and compounds belonging to this new family have been tested in vitro on both subtypes of PPAR nuclear receptors. Corresponding results indicated a strong decrease in the activity towards both subtypes, especially on PPAR. However, they have also clearly shown the central role of the bottom side chain in the activity.

Le diabète de type 2 (DT2, 90 % des diabétiques) progresse de manière spectaculaire dans les pays développés et encore plus dans les pays du tiers monde. Longtemps restreint à une population de sujets obèses ayant atteint la maturité, il touche à présent des populations de plus en plus jeunes. L’hyperglycémie à jeun et post-prandiale du patient DT2 est la résultante de deux anomalies interdépendantes, la diminution de la sensibilité des tissus-cibles à l’insuline (insulinorésistance) et l’altération de la capacité des cellules β à sécréter l’hormone. Le développement des connaissances sur la maladie font du dysfonctionnement des cellules β l’élément-clé de la détérioration de l’équilibre glycémique. La capacité d’adaptation (plasticité) anatomique (nombre et volume des cellules) et fonctionnelle (quantité d’insuline sécrétée et cinétique de la sécrétion de l’hormone) des cellules β aux besoins en insuline de l’organisme est impressionnante. Elle garantit un contrôle optimal de l’homéostasie glucidique. On comprend donc qu’un défaut de plasticité des cellules β, surtout chez des sujets ayant une demande insulinique supérieure à la normale du fait de l’insulinorésistance, concoure au développement du DT2. Il est ainsi indéniable que l’équipement en cellules β fonctionnelles (masse fonctionnelle) est altéré chez le sujet DT2 et qu’il se dégrade au cours de l’évolution de la maladie. Cette dégradation est largement liée à la détérioration de l’environnement métabolique de la cellule β résultant de l’hyperglycémie et de l’hyperlipidémie (gluco-lipotoxicité). Dans ces conditions, il est logique que les approches thérapeutiques futures du DT2 intègrent la nécessité d’augmenter la masse fonctionnelle β en ciblant les mécanismes de sa détérioration

Genetic studies in human populations and rodent models have identified regions of human chromosome 1q21–25 and rat chromosome 2 showing evidence of significant and replicated linkage to diabetes-related phenotypes. To investigate the relationship between the human and rat diabetes loci, we fine mapped the rat locus Nidd/gk2linked to hyperinsulinemia in an F2 cross derived from the diabetic (type 2) Goto-Kakizaki (GK) rat and the Brown Norway (BN) control rat, and carried out its genetic and pathophysiological characterization in BN.GK congenic strains. Evidence of glucose intolerance and enhanced insulin secretion in a congenic strain allowed us to localize the underlying diabetes gene(s) in a rat chromosomal interval of ∼3–6 cM conserved with an 11-Mb region of human 1q21–23. Positional diabetes candidate genes were tested for transcriptional changes between congenics and controls and sequence variations in a panel of inbred rat strains. Congenic strains of the GK rats represent powerful novel models for accurately defining the pathophysiological impact of diabetes gene(s) at the locus Nidd/gk2and improving functional annotations of diabetes candidates in human 1q21–23.

Diabetic pregnancy results in several metabolic and hormonal disorders, both in the embryo and the fetus of different species, including humans. Insulin is a potent modulator of brain development and is suggested to promote the differentiation and maturation of hypothalamic or related extrahypothalamic structures, which are directly involved in neural inputs to the pancreas. Because these structures are known to be specifically responsive both to insulin and glucose, we examined the effects of 48-h hyperglycemic clamps in unrestrained pregnant rats on insulin binding and glucose transporter expression in hypothalamic and extrahypothalamic-related areas of their fetal offspring. The main result was an increase in insulin binding in the ventromedial hypothalamic nucleus (VMH), the arcuate nucleus (AN), and the lateral hypothalamus (LH), and in the nucleus of the tractus solitarius (NTS) for extrahypothalamic areas (+30% in the VMH, +37% in the AN, +25.8% in the LH, and +37.3% in the NTS). The deleterious effect of brain hyperinsulinism during the late gestational stage does not seem to act through glucose transporter (GLUT) expression, inasmuch as no relationship between GLUT level and hyperinsulinism in brain areas could be observed. The specific increase in insulin binding in areas involved in the nervous control of metabolism could be a factor in the increased glucose intolerance and impairment of insulin secretion that was previously observed in the adult rats from hyperglycemic mothers.

Hyperinsulinemic rat fetuses were obtained either by repeated in utero injections of long-acting insulin (resulting in fetal hypoglycemia) or by chronically infusing intravenous glucose to the mother (resulting in fetal hyperglycemia). Fetuses were examined at term. In insulin injected fetuses (n15), surfactant (S) fraction phosphatidylcholine (PC) and dis saturated phosphatidylcholine (DSPC) were significantly decreased (3.6 ± 0.1 nmol Pi/ mg tissue; p<0.001 and 2.8 ± 0.1 nmol/mg; p<0.025, respectively) as compared with their saline-injected controls (4.8 ± 0.2 and 3.3 ± 0.1 nmol/mg, respectively, n19). However, residual (R) fraction was unchanged, and there was no difference in whole-lung phospholipids (combined S and R fractions). These results are consistent with morphological data showing a lower lamellar body area per type II cell profile in insulin-injected fetuses as compared with their controls 1.41 ± 0.13 µm2(n72) versus 1.99 ± 0.14 µm2(n129) p<0.01. Glycogen content was slightly higher in insulin-injected fetuses (18.5 ± 1.0 Mg/mg, n17) than in their controls (15.1 ±0.8 fig/mg, n18; p<0.05). In the second model, changes in S fraction PC and DSPC were similar to those observed after insulin injections 4.3 ± 0.25 and 3.4 ± 0.2 nmol Pi/mg in fetuses of glucose-infused rats (n10) versus 5.7 ± 0.45 and 4.3 ± 0.3 nmol Pi/mg, respectively, in controls (n10, p<0.05). In addition, PG was also decreased (0.24 ± 0.03 versus 0.40 ± 0.04 nmol Pi/mg, n10; p<0.01), and in contrast with insulin injections, reductions of DSPC and PG were detectable in whole lung. However, glycogen content was unchanged by glucose infusion (13.7 ±1.0 µg mg, n15 versus 14.0 ± 1.1 Mg/mg, n20 in controls). In both models, the phospholipid composition of material recovered by lung lavage was unchanged. (Pediatr Res 21 436-441,1987

Insulin and glucagon are detected in the plasma of most species early in gestation. In the fetus at term, insulin and glucagon secretion can be modified by long-term changes in glucose concentration but the responsiveness of A and B cells to glucose is lower than in the adult. The plasma insulin/glucagon molar ratio is high in the fetus at term, then decreases dramatically immediately after birth and remains low during the first hours of extrauterine life. This situation results in favored hepatic glycogen storage and prevented gluconeogenesis in utero, and sharp glycogen breakdown and active gluconeogenesis during the early postnatal period.

We investigated the effect of intravenous 2mM Troxerutine and 10mM α-Tocopherol (Vitamin E) and their combination on erythrocyte aggregation and deformability, blood viscosity and leukocyte adhesivity in rats made mildly diabetic (fasting glycemia: 10mM vs 6mM in controls; HbA1c: 6.5% vs 3% in controls) by a low dose of streptozotocin (35mg/kg) injected via the saphenous vein. In diabetic rats, as compared to controls, erythrocyte aggregation and blood viscosity were dramatically increased (disaggregation shear stress: 5.2 ± 0.4 dynes/cm2vs 3.7 ± 0.3 dynes/cm2in controls), whereas erythrocyte deformability and mesenteric blood flow were sharply decreased. Moreover, leukocyte adhesivity was significantly increased. In diabetic rats, the combination of Troxerutine and Tocopherol improved all the above cited parameters. These data show that mild diabetes in rats results in many hemorheological disorders that can be largely corrected by Troxerutine and α-Tocopherol.

Goto-Kakizaki (GK) rats are a well characterized model for non-insulin dependent diabetes mellitus (NIDDM). We have used a combination of physiological and genetic studies to identify quantitative trait loci (QTLs) responsible for the control of glucose homeostasis and insulin secretion in a F2cohort bred from spontaneously diabetic GK rats. The genetic dissection of NIDDM allowed us to map up to six independently segregating loci predisposing to hyperglycaemia, glucose intolerance or altered insulin secretion, and a seventh locus implicated in body weight. QTLs implicated in glucose tolerance and adiposity map to the same region of rat chromosome 1, and may indicate the influence of a single locus. Our study demonstrates that distinct combinations of genetic loci are responsible for different physiological characteristics associated with the diabetic phenotype in the GK rat, and it constitutes an important step for directing the search for the genetic factors involved in human NIDDM.

Recent data suggest that some imidazoline derivatives can lower plasma glucose in experimental animal models of diabetes. We studied the activity of an imidazoline S‐22068, in rat model of non‐insulin‐dependent diabetes mellitus (NIDDM) produced with a low dose of streptozotocin (35 mg kg−1, i.v.) in the adult.The respective increase over basal value in glucose (ΔG) and insulin (ΔI), and the rate of glucose disappearance (K), were measured during a 30 min intravenous glucose tolerance test. After an intraperitoneal injection of S‐22068 (24 mg kg−1), ΔG (mMmin −1) was decreased (91.67±5.83 vs 120.5±3.65; P<0.001), whereas K was increased (1.74±0.09 vs 1.18±0.05; P<0.001). Although insulinaemia was increased at time‐point 0 of the test, ΔI was unchanged.During oral glucose tolerance tests (OGTT), S‐22068 (24 mg kg−1, p.o.) improved glucose tolerance, and its efficiency was potentiated after chronic treatment (15 days). Basal glycaemia was unaffected by the treatment. Under the same conditions, a higher dose of S‐22068 (40 mg kg−1) further improved glucose tolerance without causing hypoglycaemia.Binding experiments revealed that S‐22068 displays no affinity for either adrenoceptors or the two imidazoline receptors I1or I2.These results demonstrate that S‐22068 improves glucose tolerance without causing hypoglycaemia. Thus S‐22068 represents a new potential option in the treatment of NIDDM.

The effects of canine fetal and adult testes and testicular tumors on reproductive tracts from 14.5 day old rat fetuses cultured in vitrowere investigated. Müllerian inhibiting activity (MIA) was found in fetal canine testes, confirming the lack of species specificity of the Müllerian inhibiting substance. Adult testes and testicular tumors were unable to produce regression of Müllerian ducts. The disappearance of the MIA in the adult testes in vitrocontrasted with an active secretion of testosterone. The absence of the MIA in the testicular tumors, including sertolinomas is discussed.

β-cell neogenesis triggers the generation of new β-cells from precursor cells. Neogenesis from duct epithelium is the most currently described and the best documented process of differentiation of precursor cells into β-cells. It is contributes not only to β-cell mass expansion during fetal and nonatal life but it is also involved in the maintenance of the β-cell mass in adults. It is also required for the increase in β-cell mass in situations of increase insulin demand (obesity, pregnancy). A large number of factors controlling the differentiation of β-cells has been identified. They are classified into the following main categories: growth factors, cytokine and inflamatory factors, and hormones such as PTHrP and GLP-1. The fact that intestinal incretin hormone GLP-1 exerts a major trophic role on pancreatic β-cells provides insights into the possibility to pharmacologically stimulate β-cell neogenesis. This could have important implications for the of treatment of type 1 and type 2 diabetes. Transdifferentiation, that is, the differentiation of already differentiated cells into β-cells, remains controversial.However, more and more studies support this concept. The cells, which can potentially “transdifferentiate” into β-cells, can belong to the pancreas (acinar cells) and even islets, or originate from extra-pancreatic tissues such as the liver. Neogenesis from intra-islet precursors also have been proposed and subpopulations of cell precursors inside islets have been described by some authors. Nestin positive cells, which have been considered as the main candidates, appear rather as progenitors of endothelial cells rather than β-cells and contribute to angiogenesis rather than neogenesis. To take advantage of the different differentiation processes may be a direction for future cellular therapies. Ultimately, a better understanding of the molecular mechanisms involved in β-cell neogenesis will allow us to use any type of differentiated and/or undifferentiated cells as a source of potential cell precursors.

We investigated the possible interplay between insulin and glucose signaling pathways in rat pancreatic β-cell with a special focus on the role of glucose in IRS signaling in vivo. Three groups of rats were constituted by combining simultaneous infusion during 48 h either of glucose and/or insulin, or glucose+diazoxide: Hyperglycemic- Hyperinsulinemic (HGHI), euglycemic-Hyperinsulinemic (eGHI), Hyperglycemic-euinsulinemic (HGeI). Control rats were infused with 0,9% NaCl. In HGHI and HGeI rats plasma glucose levels were maintained at 20-22 mmol/l. In eGHI rats, plasma glucose was not different from that of controls, whereas plasma insulin was much higher than in controls. In HGHI rats, IRS-2 mRNA expression, total protein and phosphorylated protein amounts were increased compared to controls. In HGeI rats, only IRS-2 mRNA expression was increased. No change was observed in eGHI rats whatever the parameter considered. In all groups, mRNA concentration of IRS-1 was similar to that of controls. The quantity of total and phosphorylated IRS- 1 protein was dramatically increased in HGHI rats and to a lesser extent in eGHI rats. Neither mRNA nor IRS-1 protein expression were modified in HGeI rats. The data suggest that glucose and insulin play at once a specific and a complementary role in islet IRSs signaling. Especially, glucose stimulates IRS-2 mRNA expression whatever the insulin status and independently of the secretory process. The differential regulation of IRS-1 and IRS-2 expressions is in agreement with their supposed different involvement in the control of β-cell growth and function.

Hypothesizing that UCP2 may influence insulin secretion by modifying the ATP/ADP ratio within pancreatic islets, we have investigated the expression of intraislet UCP2 gene in rats showing insulin oversecretion (non-diabetic Zucker fa/fa obese rats, glucose-infused Wistar rats) or insulin undersecretion (fasting and mildly diabetic rats). We found that in Zucker fa/fa obese rats, hyperinsulinemia (1222 ± 98 pmol/1 vs. 128 ± 22 pmol/1 in lean Zucker rats) was accompanied by a significant increase in UCP2 mRNA levels. In rat submitted to a 5 day infusion with glucose, hyperinsulinemia (1126 ± 101 pmol/l vs. 215 ± 25 pmol/1 in Wistar control rats), coincided with an enhanced intraislet UCP2 gene expression, whereas a 8h or a 2 day-infusion did not induce significant changes in UCP2 mRNA expression. In rats made hypoinsulinemic and mildly diabetic by the injection of a low dose of streptozotocin, and in 4-day-fasting rats (plasma insulin 28 ± 5 pmol/1) UCP2 gene expression was sharply decreased. A 3-day-fast was ineffective. The data show the existence of a time-dependent correlation between islet mRNA UCP2 and insulin that may be interpreted as an adaptative response to prolonged insulin excess.