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Background Iatrogenic peripheral hyperinsulinemia, resulting from peripheral insulin administration in type 1 diabetes, may increase insulin resistance and impair endothelial function. We hypothesized that lowering iatrogenic peripheral hyperinsulinemia via a one-week, reduced-carbohydrate diet (RCD) would improve insulin sensitivity and endothelial function compared with an isocaloric standard carbohydrate diet (SCD). Methods In this randomized, single-blinded, crossover trial, we studied 12 adults with type 1 diabetes. Participants completed both a one-week RCD and a one-week SCD, separated by a three-week washout. After each intervention, we measured insulin sensitivity using a hyperinsulinemic–euglycemic clamp and assessed endothelial function via brachial-artery flow-mediated vasodilation (FMD). Results The RCD reduced total daily insulin doses by 16% compared with the SCD. Despite this reduction, insulin sensitivity did not improve (median glucose infusion rates: RCD 8.1 mg/kg FFM/min [IQR 6.7–10.1] vs. SCD 8.6 mg/kg FFM/min [7.0–11.0], p  = 0.47). Similarly, endothelial function did not differ significantly (FMD after RCD 7.50% [3.25–15.5] vs. SCD 9.81% [4.96–14.3], p  = 0.91). Although higher insulin doses correlated with lower insulin sensitivity under both conditions, lowering insulin dose through the RCD alone did not yield measurable improvements. Conclusions Although a one-week RCD significantly lowered insulin requirements, it failed to enhance insulin sensitivity or endothelial function in adults with type 1 diabetes. These findings underscore the complex and dynamic relationship between insulin exposure and cardiometabolic health. Similar basal overnight insulin delivery may have masked potential benefits by the time of testing, highlighting the need for further studies to refine strategies aimed at mitigating hyperinsulinemia’s adverse effects. Trial registration ClinicalTrials.gov NCT04118374. Graphical abstract

Abstract Context Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood. Objective We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease. Methods We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children. Results We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy. Conclusion We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis.

Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center. Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. Except for Macrophage Inflammatory Protein-1β (MIP-1β), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.

Glycaemic index (GI) is used as an indicator to guide consumers in making healthier food choices. We compared the GI, insulin index (II), and the area under the curve for blood glucose and insulin as glucose (GR) and insulin responses (IR) of a newly developed liquid nutritional formula with one commercially available liquid product with different types of carbohydrates. We then evaluated the glucose and insulin responses of two test foods with comparable energy density and protein percentage but presented in different food forms (liquid vs. solid). Fourteen healthy women participated in the study. GI, II, GR, and IR were assessed after (independent) consumption of two liquid products and a solid breakfast meal. The two liquid foods showed comparable GI, whilst the liquid form appeared to produce lower median GI (25 vs. 54), and II (52 vs. 98) values compared to the solid breakfast (p < 0.02). The median GR and IR for solid breakfast were respectively 44% and 45% higher compared to the liquid product (p < 0.02). Liquid formulas with different carbohydrate qualities produced comparable glucose responses, while foods with comparable energy density and protein percentage but different food form elicited differential effects on GI, II, GR, and IR. Nutrient quality and food form need to be taken into consideration when developing low GI products to manage glycaemic responses.

Consumption of red raspberries has been reported to exert acute beneficial effects on postprandial glycemia, insulinemia, triglyceridemia, and cytokine levels in metabolically disturbed subjects. In a two-arm parallel-group, randomized, controlled trial, 59 subjects with overweight or abdominal obesity and with slight hyperinsulinemia or hypertriglyceridemia were randomized to consume 280 g/day of frozen raspberries or to maintain their usual diet for 8 weeks. Primary analyses measured metabolic differences between the groups. Secondary analyses performed with omics tools in the intervention group assessed blood gene expression and plasma metabolomic changes following the raspberry supplementation. The intervention did not significantly affect plasma insulin, glucose, inflammatory marker concentrations, nor blood pressure. Following the supplementation, 43 genes were differentially expressed, and several functional pathways were enriched, a major portion of which were involved in the regulation of cytotoxicity, immune cell trafficking, protein signal transduction, and interleukin production. In addition, 10 serum metabolites were found significantly altered, among which β-alanine, trimethylamine N-oxide, and bioactive lipids. Although the supplementation had no meaningful metabolic effects, these results highlight the impact of a diet rich in raspberry on the immune function and phospholipid metabolism, thus providing novel insights into potential immune-metabolic pathways influenced by regular raspberry consumption.

Congenital hyperinsulinism (CHI) is a heterogeneous disorder of insulin dysregulation, leading to hypoglycemia. This study describes the clinical characteristics, genetics, and management of CHI in Argentina. We retrospectively reviewed 70 probands diagnosed with CHI (2008-2021) at multiple centres across Argentina. Clinical, biochemical, imaging, and treatment data were analyzed. Genetic testing was performed in 49 probands using Sanger and targeted next-generation sequencing of CHI-related genes. Transient CHI was identified in 23/70 (33%) probands, with a median duration of 2 months. Risk factors for perinatal stress-induced hyperinsulinism (PSHI) were present in 85% of transient cases. Persistent CHI was diagnosed in 44/70 (63%) individuals, of whom 31 responded to diazoxide. Late-onset CHI (diagnosed >3 years) was identified in 3 children. A pathogenic variant was detected in 19/49 (39%) probands, all had persistent CHI. ABCC8 variants were most common accounting for 68% (13/19) of diagnoses. Imaging in 17 cases revealed focal disease in 8, diffuse disease in 8, and atypical disease in 1 individual. Seven individuals with focal disease underwent lesionectomy, which was curative in 5 (71%). Three children with diffuse disease required near-total pancreatectomy, with one developing postoperative diabetes. This study provides the largest CHI cohort reported from South America and highlights the clinical and genetic heterogeneity of the condition. Transient CHI was often associated with PSHI risk factors, while persistent CHI was predominantly linked to K-ATP channel variants. The findings underscore the importance of genetics and imaging for CHI management and emphasize the need for increased access to molecular diagnostics.

High cereal fibre intake is associated with reduced risk for type 2 diabetes, but wheat fibre had little or no effect on glycaemic control or oral glucose tolerance in clinical trials lasting 4–12 weeks. To explain this discrepancy, we hypothesised that colonic adaptation to increased wheat fibre intake takes many months but eventually results in increased SCFA production and glucagon-like peptide-1 (GLP-1) secretion. Thus, the primary objective was to determine the time-course of the effects of increased wheat fibre intake on plasma acetate, butyrate and GLP-1 concentrations in hyperinsulinaemic human subjects over 1 year. Subjects with fasting plasma insulin ≥ 40 pmol/l were randomly assigned by computer to receive either a high-wheat fibre cereal (fibre group; 24 g fibre/d; twenty assigned; six dropped out, fourteen included) or a low-fibre cereal (control group; twenty assigned; six dropped-out, fourteen included) daily for 1 year. Acetate, butyrate and GLP-1 were measured during 8 h metabolic profiles performed every 3 months. There were no differences in body weight in the fibre group compared with the control group. After 9 months baseline-adjusted mean 8 h acetate and butyrate concentrations were higher on the high-fibre than the control cereal (P < 0·05). After 12 months on the high-fibre cereal, baseline-adjusted mean plasma GLP-1 was 1·3 (95 % CI 0·4, 2·2) pmol/l (P < 0·05) higher than at baseline (about 25 % increase) and 1·4 (95 % CI 0·1, 2·7) pmol/l (P < 0·05) higher than after 12 months on control. It is concluded that wheat fibre increased SCFA production and GLP-1 secretion in hyperinsulinaemic humans, but these effects took 9–12 months to develop. Since GLP-1 may increase insulin sensitivity and secretion, these results may provide a mechanism for the epidemiological association between high cereal fibre intake and reduced risk for diabetes.

Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.This Review discusses the current understanding of how insulin and insulin receptor signalling contribute to cancer growth, in the context of the rising prevalence of obesity and diabetes worldwide and the realization that hyperinsulinaemia may contribute to therapeutic failures.

Aims/hypothesisCongenital hyperinsulinism caused by mutations in the KATP-channel-encoding genes (KATPHI) is a potentially life-threatening disorder of the pancreatic beta cells. No optimal medical treatment is available for patients with diazoxide-unresponsive diffuse KATPHI. Therefore, we aimed to create a model of KATPHI using patient induced pluripotent stem cell (iPSC)-derived islets.MethodsWe derived iPSCs from a patient carrying a homozygous ABCC8V187D mutation, which inactivates the sulfonylurea receptor 1 (SUR1) subunit of the KATP-channel. CRISPR-Cas9 mutation-corrected iPSCs were used as controls. Both were differentiated to stem cell-derived islet-like clusters (SC-islets) and implanted into NOD-SCID gamma mice.ResultsSUR1-mutant and -corrected iPSC lines both differentiated towards the endocrine lineage, but SUR1-mutant stem cells generated 32% more beta-like cells (SC-beta cells) (64.6% vs 49.0%, p = 0.02) and 26% fewer alpha-like cells (16.1% vs 21.8% p = 0.01). SUR1-mutant SC-beta cells were 61% more proliferative (1.23% vs 0.76%, p = 0.006), and this phenotype could be induced in SUR1-corrected cells with pharmacological KATP-channel inactivation. The SUR1-mutant SC-islets secreted 3.2-fold more insulin in low glucose conditions (0.0174% vs 0.0054%/min, p = 0.0021) and did not respond to KATP-channel-acting drugs in vitro. Mice carrying grafts of SUR1-mutant SC-islets presented with 38% lower fasting blood glucose (4.8 vs 7.7 mmol/l, p = 0.009) and their grafts failed to efficiently shut down insulin secretion during induced hypoglycaemia. Explanted SUR1-mutant grafts displayed an increase in SC-beta cell proportion and SC-beta cell nucleomegaly, which was independent of proliferation.Conclusions/interpretationWe have created a model recapitulating the known pathophysiology of KATPHI both in vitro and in vivo. We have also identified a novel role for KATP-channel activity during human islet development. This model will enable further studies for the improved understanding and clinical management of KATPHI without the need for primary patient tissue.

Background The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program. Methods Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m 2 , underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry. Results Weight loss averaged −8.3 ± 0.6 % of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9 %, P = 0.04) and exogenous insulin clearance (by 12 ± 5 %, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by −12 ± 5 %, whole-body norepinephrine spillover rate by −14 ± 8 %, and MSNA by −9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = −0.63, P = 0.01) which explained 40 % of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64 % of the variance. Conclusions Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850