Prediabetes and type 2 diabetes have been associated with more severe metabolic dysfunction-associated steatotic liver disease (MASLD), but not all individuals have the same risk and the metabolic drivers remain incompletely understood. To understand why, we examined the roles of obesity, adipose tissue dysfunction and insulin resistance in the development of significant liver fibrosis (fibrosis stage ≥F2) in adults across the glycaemic spectrum. We performed a prospective, cross-sectional study in a real-world setting of adults attending primary care or endocrinology/diabetes clinics. Transient elastography was used to diagnose steatosis (controlled attenuation parameter ≥274 dB/m) and clinically significant liver fibrosis (vibration-controlled transient elastography liver stiffness measurement ≥8.2 kPa). When ≥F2 was suspected, MR-based imaging or liver biopsy was used to improve stratification. MASLD and significant fibrosis were compared across glycaemic and BMI categories and severity of insulin resistance (HOMA-IR; predominantly hepatic) and adipose tissue insulin resistance (assessed by adipose tissue insulin resistance [Adipo-IR]). Among the 1446 participants, the prevalence of MASLD increased across glycaemic categories from 39
Breastfeeding is associated with metabolic benefits for women with type 2 diabetes and their infants, yet breastfeeding rates in these women are poorly described. Obesity is associated with type 2 diabetes and lower breastfeeding rates, making it difficult to disentangle the effects of type 2 diabetes vs obesity on breastfeeding. The primary objective was to examine breastfeeding rates in women with type 2 diabetes compared with normoglycaemic women with either (1) matched BMI or (2) normal BMI. The secondary objective was to examine variables associated with breastfeeding. Pregnant women with type 2 diabetes (cases) or normoglycaemia (controls) were prospectively recruited. Each case was matched with two controls by age and parity and either (1) matched or (2) normal (18–25 kg/m2) BMI. Data were collected from in-person surveys antenatally, medical records and a 4 month postpartum telephone survey. Analysis included descriptive and inferential statistics. Four months of breastfeeding data were available for 29 women with type 2 diabetes, 29 BMI-matched controls and 28 normal-BMI controls. Breastfeeding rates were similar in women with type 2 diabetes and BMI-matched controls, but both rates were significantly lower than those in normal-BMI controls. ‘Full’ breastfeeding rates were 24
Paracrine signalling by hormone-producing endocrine cells potentially influences pancreatic development, but this feedback regulation remains poorly understood. Here, we investigated the roles of gastrin (GAST), cholecystokinin (CCK) and their receptor cholecystokinin B receptor (CCKBR) during human pancreatic development. Human iPSCs were differentiated stepwise into definitive endoderm and then the pancreatic endocrine lineage. To assess CCKBR function, CRISPR/Cas9 was used to generate CCKBR-knockout iPSC lines. We profiled transcriptional states by bulk and single-cell RNA-seq with computational analyses, and complemented these with biochemical assays, flow cytometry (FACS) and confocal microscopy. CCKBR expression peaked during definitive endoderm formation and progressively declined during differentiation, remaining detectable in pancreatic progenitors but largely absent from the endocrine lineage. By contrast, GAST and CCK were expressed only transiently during pancreatic progenitor and endocrine lineage formation. Pharmacological activation/inhibition and genetic knockout implicated CCKBR signalling during definitive endoderm formation. Consistently, bulk RNA-seq indicated that CCKBR deletion triggered ectodermal- and mesodermal-associated transcriptional programs and diminished pancreatic lineage specification. During pancreatic induction and lineage formation, sustained CCKBR activation with GAST or CCK attenuated endocrinogenesis and promoted epithelial structure formation. Further analysis revealed the emergence of a pancreatic ductal-like cell formation under prolonged CCKBR stimulation. This study provides mechanistic evidence that the GAST/CCK–CCKBR axis is functionally important during human endoderm and pancreas development. This pathway is repeatedly required during in vitro pluripotent stem cell differentiation, regulating germ-layer formation as well as ductal vs endocrine fate decisions. These findings support the optimisation of pancreatic differentiation protocols and inform future studies on whether this axis contributes to human pancreas development and disease.
We previously reported that expression of nuclear factor erythroid 2-related factor 2 (NRF2) is upregulated in the renal tubules of humans with diabetes and in mouse models of diabetes. We hypothesised that Nrf2 deletion would ameliorate renal hyperfiltration and kidney injury in Akita mice (a model of type 1 diabetes). Akita Nrf2RT knockout (KO) mice were generated by cross-breeding tubule-specific (Pax8)-Cre mice with Akita Nrf2 floxed mice on a C57BL/6 background. Male non-diabetic control mice (Nrf2fl/fl), Nrf2RT KO mice, Akita Nrf2fl/fl mice and Akita Nrf2RT KO mice were studied up to the age of 20 weeks (n=8 per group). The glomerular filtration rate (GFR), kidney hypertrophy, tubular injury score, glomerular basement membrane thickness, podocyte loss and foot process effacement and urinary albumin–creatinine ratio were significantly increased in Akita Nrf2fl/fl mice and were markedly reduced in Akita Nrf2RT KO mice compared with the corresponding control mice. Attenuation of afferent arteriole vasodilation and efferent arteriole vasoconstriction was observed in Akita Nrf2RT KO mice compared with Akita Nrf2fl/fl mice. Furthermore, downregulation of sodium–glucose co-transporter 2 (SGLT2) and angiotensinogen expression in renal proximal tubules was observed in Akita Nrf2RT KO mice compared with Akita Nrf2fl/fl mice. Treatment of Akita Nrf2RT KO mice with a selective A1 adenosine receptor inhibitor increased GFR and fractional excretion of glucose, suggesting that enhanced adenosine signalling may contribute to the altered renal haemodynamics through tubuloglomerular feedback and reduced glomerular injury associated with RT-specific Nrf2 deletion. These findings suggest that tubular NRF2 plays an important role in the progression of diabetic kidney disease in Akita mice through modulation of the GFR and expression of SGLT2 and angiotensinogen in renal proximal tubules and tubuloglomerular feedback.
Prediabetes is heterogeneous, with subtypes defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or HbA1c, each with different risks of progression to type 2 diabetes. We compared progression across these subtypes, and evaluated the benefit of adding insulin secretion and sensitivity to risk stratification. We analysed 7186 Korean adults aged 40–69 years from the community-based Korean Genome and Epidemiology Study, who were followed for up to 20 years with biennial (every 2 years) oral glucose tolerance tests and HbA1c. Prediabetes was classified as IFG, IGT or HbA1c-defined, and further stratified by insulinogenic index (IGI) and insulin sensitivity index (ISI). Cox regression was used to estimate diabetes risk, and multistate Markov models were used to assess annual transition probabilities and time spent in each state. Compared with normoglycaemia, the adjusted hazard ratios (aHRs) were 5.84 (95
