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Aims/hypothesis: Pancreatic beta cell dedifferentiation, transdifferentiation into other islet cells and apoptosis have been implicated in beta cell failure in type 2 diabetes, although the mechanisms are poorly defined. The endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) is a major regulator of the unfolded protein response. XBP1 expression is reduced in islets of people with type 2 diabetes, but its role in adult differentiated beta cells is unclear. Here, we assessed the effects of Xbp1 deletion in adult beta cells and tested whether XBP1-mediated unfolded protein response makes a necessary contribution to beta cell compensation in insulin resistance states., Methods: Mice with inducible beta cell-specific Xbp1 deletion were studied under normal (chow diet) or metabolic stress (high-fat diet or obesity) conditions. Glucose tolerance, insulin secretion, islet gene expression, alpha cell mass, beta cell mass and apoptosis were assessed. Lineage tracing was used to determine beta cell fate., Results: Deletion of Xbp1 in adult mouse beta cells led to beta cell dedifferentiation, beta-to-alpha cell transdifferentiation and increased alpha cell mass. Cell lineage-specific analyses revealed that Xbp1 deletion deactivated beta cell identity genes (insulin, Pdx1, Nkx6.1, Beta2, Foxo1) and derepressed beta cell dedifferentiation (Aldh1a3) and alpha cell (glucagon, Arx, Irx2) genes. Xbp1 deletion in beta cells of obese ob/ob or high-fat diet-fed mice triggered diabetes and worsened glucose intolerance by disrupting insulin secretory capacity. Furthermore, Xbp1 deletion increased beta cell apoptosis under metabolic stress conditions by attenuating the antioxidant response., Conclusions/interpretation: These findings indicate that XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and is required for beta cell compensation and prevention of diabetes in insulin resistance states., (© 2022. The Author(s).)

Every 10 years, the Diabetic Pregnancy Study Group, a study group of the EASD, conducts an audit meeting to review the achievements of the preceding decade and to set the directions for research and clinical practice improvements for the next decade. The most recent meeting focused on the following areas: improving pregnancy outcomes for women with pregestational type 1 diabetes and type 2 diabetes; the influence of obesity and gestational diabetes on pregnancy outcomes; the determinants and assessment of fetal growth and development; and public health issues, including consideration of transgenerational consequences and economic burden. The audit meeting also considered the likely impact of 'omics' on research within the field and the potential of these technologies to enable precision-medicine approaches to management. Through sharing of the findings and ideas of audit meeting participants, the DPSG hopes to promote networking, research and advances in clinical care, to improve outcomes for all women and their offspring affected by diabetes and obesity in pregnancy.

Adverse neonatal outcomes continue to be high for mothers with type 1 and type 2 diabetes, and are far from eliminated in mothers with gestational diabetes mellitus. This is often despite seemingly satisfactory glycaemic control in the latter half of pregnancy. Here we argue that this could be a consequence of the early establishment of fetal hyperinsulinaemia, a driver that exaggerates the fetal glucose steal. Essentially, fetal hyperinsulinaemia, through its effect on lowering fetal glycaemia, will increase the glucose concentration gradient across the placenta and consequently the glucose flux to the fetus. While the steepness of this gradient and glucose flux will be greatest at times when maternal hyperglycaemia and fetal hyperinsulinaemia coexist, fetal hyperinsulinaemia will favour a persistently high glucose flux even at times when maternal blood glucose is normal. The obvious implication is that glycaemic control needs to be optimised very early in pregnancy to prevent the establishment of fetal hyperinsulinaemia, further supporting the need for pre-pregnancy planning and early establishment of maternal glycaemic control. An exaggerated glucose steal by a hyperinsulinaemic fetus could also attenuate maternal glucose levels during an OGTT, providing an explanation for why some mothers with fetuses with all the characteristics of diabetic fetopathy have 'normal' glucose tolerance.

Aims/hypothesis: The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model., Methods: Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured., Results: ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression., Conclusions/interpretation: Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.

Aims/hypothesis: The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes., Materials and Methods: NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats., Results: Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent., Conclusions/interpretation: The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

Aims/hypothesis: Gestational diabetes is associated with complications for the offspring before, during and after delivery. Poor maternal glucose control, however, is a weak predictor of these complications. Given its position at the interface of the maternal and fetal circulations, the placenta possibly plays a crucial part in protecting the fetus from adverse effects from the maternal diabetic milieu. We hypothesised that gestational diabetes may result in changes in placental function, particularly with respect to the uptake, transfer, and/or utilisation of glucose. We aimed to examine glucose transport and utilisation in intact human placental lobules from women with gestational diabetes and those from normal pregnancies., Method: Dual perfusion of an isolated placental lobule was done on placentae from diet treated gestational diabetic (n = 7) and normal pregnant patients (n = 9) using maternal glucose concentrations of 4, 8, 16 and 24 mmol/l in random order over a 4-h experiment. Results were expressed in micromol x min(-1) x g(-1)., Results: D-glucose uptake from the maternal circulation (control 0.492 vs gestational diabetes mellitus 0.248, at 8 mmol/l maternal glucose), D-glucose utilisation by the placenta (0.255 vs 0.129), D-glucose transfer to the fetal circulation (direct 0.979 vs 0.402; net transfer 0.269 vs 0.118) and L-lactate maternal release into both the fetal (0.052 vs 0.042) and maternal (0.255 vs 0.129) circulation were significantly reduced during in vitro perfusion of placentae from patients with gestational diabetic pregnancies. Transfer of 3H-L-glucose also significantly reduced in the diabetic group (8.1% vs 2.6%)., Conclusion/interpretation: These results suggest that placental transport and metabolism of D-glucose is altered during gestational diabetes.

The aim of this study was to determine the effects of late pregnancy on the ability of insulin to suppress maternal hepatic glucose production in the rat. Unlike in most previous studies, suppression of hepatic glucose production was measured at levels of glycaemia above the relatively hypoglycaemic basal pregnant level. Glucose kinetics were measured using steady-state tracer methodology in chronically catheterised, conscious virgin control and pregnant rats, firstly, during basal and low-dose hyperinsulinaemic euglycaemic clamp conditions and secondly, during a three-step glucose infusion protocol (glucose infusion rates of 0, 60 and 150 mumol.kg-1. min-1). During the clamps, plasma glucose levels were not different (6.1 +/- 0.4 vs 6.5 +/- 0.3 mmol/l, pregnant vs virgin; N.S.), but plasma insulin levels were higher in the pregnant rats (242 +/- 30 vs 154 +/- 18 pmol/l. pregnant vs virgin; p < 0.05) most probably due to stimulated endogenous insulin release in this group. Hepatic glucose production was suppressed from basal levels by 41% in virgin and 90% in pregnant rats. During the glucose infusion studies, at matched insulin levels (147 +/- 10 vs 152 +/- 14 pmol/l), but at plasma glucose levels which were much lower in the pregnant rats (5.5 +/- 0.2 vs 8.4 +/- 0.6 mmol/l, pregnant vs virgin; p < 0.0001), hepatic glucose production was shown to be suppressed by a similar degree in both groups (41 +/- 5 vs 51 +/- 5% from basal, pregnant vs virgin; N.S.). Both the plasma insulin and percentage suppression of hepatic glucose production dose responses to plasma glucose were markedly shifted to the left indicating that the plasma glucose set point is lowered in pregnancy. In conclusion, suppression of hepatic glucose production by insulin is not impaired and the set point for plasma glucose homeostasis is lowered during late pregnancy in the rat.

The aim of this study was to determine the extent to which a feto-placental glucose steal phenomenon contributes to the process of maternal metabolic adaptation to late pregnancy. Glucose metabolism was studied in virgin control, pregnant rats and virgin rats with a phlorizin-induced model of the feto-placental glucose steal phenomenon. Whole body glucose kinetics and glucose uptake into individual tissues were measured in anaesthetised rats basally and during hyperinsulinaemic euglycaemic clamps. The basal glucose metabolism of the pregnant rats was closely mimicked by the phlorizin-treated rats. Basal plasma glucose was 39% and 38% lower (p < 0.0001 for both); hepatic glucose production was 21% and 26% higher (p < 0.05 for both); and plasma glucose clearance was 109% and 104% higher (p < 0.0001 for both) in the pregnant and phlorizin-treated rats, respectively, compared to the control rats. Basal glucose uptake into peripheral tissues was lower in both the pregnant and phlorizin-treated compared to the control rats, being most evident in heart (p < 0.01 for both) and brown adipose tissue (p < 0.001 for both). In the clamp studies, impairment of glucose uptake into skeletal muscle was observed in both the pregnant and phlorizin-treated rats compared to the control rats. In conclusion, the feto-placental glucose steal phenomenon is a major contributing factor to postabsorptive glucose metabolism in late pregnancy. This phenomenon also contributes to the impairment of maternal insulin-stimulated peripheral glucose uptake.