Beta-cell compensation and gestational diabetes.

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal ß-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed ß-cell compensation, is essential for maintaining normal maternal metabolism. ß-cell compensation culminates in the expansion of ß-cell mass and augmentation of ß-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, ß-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational ß-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How ß-cells compensate for pregnancy and what causes ß-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that ß-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to ß-cell compensation for pregnancy. We will provide mechanistic insights into ß-cell decompensation in the etiology of GDM.

SetD7 (Set7/9) is a novel target of PPARγ that promotes the adaptive pancreatic ß-cell glycemic response.

Loss of functional pancreatic ß-cell mass leads to type 2 diabetes (T2D), attributable to modified ß-cell-dependent adaptive gene expression patterns. SetD7 is a histone methyltransferase enriched in pancreatic islets that mono- and dimethylates histone-3-lysine-4 (H3K4), promoting euchromatin modifications, and also maintains the regulation of key ß-cell function and survival genes. However, the transcriptional regulation of this important epigenetic modifier is unresolved. Here we identified the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARγ) as a major transcriptional regulator of SetD7 and provide evidence for direct binding and functionality of PPARγ in the SetD7 promoter region. Furthermore, constitutive shRNA-mediated PPARγ knockdown in INS-1 ß-cells or pancreas-specific PPARγ deletion in mice led to downregulation of SetD7 expression as well as its nuclear enrichment. The relevance of the SetD7-PPARγ interaction in ß-cell adaptation was tested in normoglycemic 60% partial pancreatectomy (Px) and hyperglycemic 90% Px rat models. Whereas a synergistic increase in islet PPARγ and SetD7 expression was observed upon glycemic adaptation post-60% Px, in hyperglycemic 90% Px rats, islet PPARγ, and PPARγ targets SetD7 and Pdx1 were downregulated. PPARγ agonist pioglitazone treatment in 90% Px rats partially restored glucose homeostasis and ß-cell mass and enhanced expression of SetD7 and Pdx1. Collectively, these data provide evidence that the SetD7-PPARγ interaction serves as an important element of the adaptive ß-cell response.

Changes in ß-Cell Function in Offspring of Type-2 Diabetic Patients, as per Fasting and Two-Hour Plasma Glucose Levels.

Background The changes in ß-cell function in high-risk populations who are apparently in the normal glucose tolerant stage are still under investigation for designing earlier prevention strategies. This study analyzes changes in ß-cell function and insulin sensitivity across fasting and two-hour glucose categories spanning normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), in offspring of subjects with type-2 diabetes mellitus (T2DM) compared to the controls without a known family history of T2DM. Methods Offspring of T2DM patients (cases) and individuals without a family history of T2DM (controls) were the subjects for this cross-sectional study. All participants underwent a 75 g oral glucose tolerance test and blood samples were collected for plasma glucose, insulin, C-peptide and proinsulin, at zero, 30, 60, and 120 minutes.  Results A total of 358 cases (age 23.0 ± 10.8 years, 54% males) and 287 controls (age 28.4 ± 8.10 years, 65% males) were the subjects of this study. Cases and controls were divided into subgroups based on fasting and two-hour glucose categories spanning NGT to IGT. Compared to the reference category of controls (< 80 mg/dL for fasting glucose and < 84 mg/dL for two-hour glucose), cases with IGT had ~60% decline in both ß-cell compensation (as measured as disposition index {0-120}) and insulin sensitivity (as measured as whole-body insulin sensitivity index {0-120}); adjusted for age, gender, and body mass index. From lower to higher fasting and two-hour glucose categories, there was a continuous and significant decline in ß-cell compensation in both cases and controls. Significant reduction in first-phase insulin secretion, as measured as insulinogenic (0-30) index, was only observed among two-hour glucose categories, not among the fasting glucose categories. In the transition from late NGT cases to IGT cases, there was a significant decline in ß-cell compensation, first-phase insulin secretion (more prominent than a decline in overall ß-cell secretion) and the changes in whole-body insulin sensitivity were not statistically significant. Conclusions The decline in ß-cell compensation was continuous and significant in offspring of subjects with type-2 diabetes and controls without a known family history of diabetes from early normal glucose tolerant ranges to impaired glucose tolerant ranges. Compared to the strictest glucose controlled category of controls, approximately 60% decline was observed in ß-cell compensation and insulin sensitivity, in impaired glucose tolerant offspring of subjects with type-2 diabetes mellitus.

Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is characterized by glycemia and insulin disorders. Bile acids (BAs) have emerged as vital signaling molecules in glucose metabolic regulation. BA change in GDM is still unclear, which exerts great significance to illustrate the change of BAs in GDM. GDM patients and normal pregnant women were enrolled during the oral glucose tolerance test (OGTT) screening period. Fasting serums were sampled for the measurement of BAs. BA metabolism profiles were analyzed in both pregnant women with GDM and those with normal glucose tolerance (NGT). Delivery characteristics, delivery gestational age, and infant birthweight were extracted from medical records. GDM patients presented distinctive features compared with NGT patients, including higher body mass index (BMI), elevated serum glucose concentration, raised insulin (both fasting and OGTT), and increased hemoglobin A1c (HbA1c) levels. Higher homeostasis model assessment of insulin resistance (HOMA-IR) and decreased ß-cell compensation (i.e., oral disposition index (DIo)) were also prevalent in this group. Total BAs (TBAs) remained stable, but glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) levels declined significantly in GDM. GDCA was inversely correlated with HOMA-IR and positively correlated with DIo. No obvious differences in clinical outcome between the GDM and NGT groups were observed. However, GDM patients with high HOMA-IR and low DIo tended to have a higher cesarean delivery rate and younger delivery gestational age. In conclusion, GDCA provides a valuable biomarker to evaluate HOMA-IR and DIo, and decreased GDCA levels predict poorer clinical outcomes for GDM.

Metformin Preserves ß-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats.

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic ß-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and ß-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on ß-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human ß-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on ß-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited ß-cell glucose-stimulated insulin secretion in vitro, stimulation of ß-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, ß-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress ß-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on ß-cell function or cell mass and, instead, early metformin treatment may help protect ß-cells from exhaustion and decompensation.

Loss of EGR-1 uncouples compensatory responses of pancreatic ß cells.

Rationale: Subjects unable to sustain ß-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence ß-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for ß-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of ß-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of ß-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.

ß-Cell compensation concomitant with adaptive endoplasmic reticulum stress and ß-cell neogenesis in a diet-induced type 2 diabetes model.

Insulin-secreting pancreatic ß-cells adapt to obesity-related insulin resistance via increases in insulin secretion and ß-cell mass. Failed ß-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of ß-cell compensation are not fully understood. Our previous study reported changes in ß-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other ß-cell adaptive responses, including glucose metabolism and ß-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of ß-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in ß-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative ß-cell growth as a mechanism of ß-cell mass adaptation. In contrast, decreased neogenesis and ß-cell dedifferentiation were observed in ß-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of ß-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for ß-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. ß-Cell neogenesis but not proliferation contributes to ß-cell mass adaptation.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in ß-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the ß-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal ß-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal ß-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous ß-cells would have an impaired ability to respond to stress. Indeed, we observed that ß-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.