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Dietary insulin index directly estimates the postprandial insulin secretion potential of foods, whereas empirical dietary index for hyperinsulinemia (EDIH) assesses insulinemic potential of usual diets based on fasting plasma C-peptide, and is primarily reflective of insulin resistance. It is unknown whether these insulin-related indices are predictive of an integrated measure of insulin secretion. We conducted a cross-sectional analysis that included 293 non-diabetic men with 24-hour urinary C-peptide data from the Men’s Lifestyle Validation Study. EDIH, dietary insulin index, and dietary insulin load were calculated using validated food frequency questionnaires. We conducted multivariable-adjusted linear regression to estimate relative and absolute concentrations of 24-hour urinary C-peptide. In multivariable-adjusted models, we found a significant positive association between all three insulin-related dietary indices and 24-hour urinary C-peptide (P<0.05). Relative concentrations of 24-hour urinary C-peptide per 1-standard deviation increase in insulin-related dietary indices were: 1.12 (95% confidence interval (CI), 1.02, 1.23) for EDIH, 1.18 (95% CI, 1.07, 1.29) for dietary insulin index and 1.16 (95% CI, 1.06, 1.27) for dietary insulin load. When we further adjusted for body mass index (BMI), the association was attenuated for EDIH, to 1.07 (95% CI, 0.98, 1.16), and remained unchanged for dietary insulin index and dietary insulin load. In conclusion, EDIH, dietary insulin index, and dietary insulin load were predictive of integrated insulin secretion assessed by 24-hour urinary C-peptide. Findings after adjustment for BMI appear to confirm the relation of EDIH to insulin resistance and dietary insulin index/load to insulin secretion; the respective constructs of the two dietary indices.

Background Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses. Hypothesis/Objective Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses. Animals Eight Standardbred geldings. Methods A PK study was performed followed by a placebo‐controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography‐mass‐spectrometry. PK indices were estimated by fitting a 2‐compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed‐effects linear regression. Sirolimus was then administered to 4 horses with dexamethasone‐induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment. Results Median (range) maximum sirolimus concentration was 277.0 (247.5‐316.06) ng/mL at 5 (5‐10) min and half‐life was 3552 (3248‐4767) min. Mean (range) oral bioavailability was 9.5 (6.8‐12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7‐7.0] μIU/mL) was 37 (−5 to 54)% less than placebo (8.7 [5.8‐13.7] μIU/mL, P = .03); and at 120 min (10.2 [8.4‐12.2] μIU/mL) was 28 (−15 to 53)% less than placebo (14.9 [8.4‐24.8] μIU/mL, P = .02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment. Conclusion and Clinical Importance Sirolimus decreased the insulinemic response to glucose and warrants further investigation.

Abstract Obesity and diabetes have both been associated with an increased risk of cancer. In the face of increasing obesity and diabetes rates worldwide, this is a worrying trend for cancer rates. Factors such as hyperinsulinemia, chronic inflammation, antihyperglycemic medications, and shared risk factors have all been identified as potential mechanisms underlying the relationship. The most common obesity- and diabetes-related cancers are endometrial, colorectal, and postmenopausal breast cancers. In this review, we summarize the existing evidence that describes the complex relationship between obesity, diabetes, and cancer, focusing on epidemiological and pathophysiological evidence, and also reviewing the role of antihyperglycemic agents, novel research approaches such as Mendelian Randomization, and the methodological limitations of existing research. In addition, we also describe the bidirectional relationship between diabetes and cancer with a review of the evidence summarizing the risk of diabetes following cancer treatment. We conclude this review by providing clinical implications that are relevant for caring for patients with obesity, diabetes, and cancer and provide recommendations for improving both clinical care and research for patients with these conditions. Graphical Abstract Graphical Abstract

In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.

Hypoglycemia in people without diabetes can be caused by a variety of factors and may become life-threatening if compensatory mechanisms are overwhelmed. We present a case of postprandial hypoglycemia associated with a heterozygous insulin receptor (INSR) gene variant, G1146R, in an 82-year-old Caucasian man with glucose intolerance and an extensive family history of similar symptoms. His hypoglycemia worsened with advancing age and eventually required a continuous blood glucose sensor with alarms to avoid severe hypoglycemia. This INSR variant is predicted to disrupt the autophosphorylation function of the receptor and was previously reported in an individual with severe insulin resistance presenting in childhood, but who did not experience hypoglycemia. This case highlights the clinical variability of INSR gene variants and may lead to reclassification of G1146R INSR, currently a variant of uncertain significance, as a likely pathogenic variant.

Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic liver disease in Western countries and affects approximately 25% of the adult population. Since NAFLD is frequently associated with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it is generally considered as the hepatic manifestation of the metabolic syndrome. In addition to its potential to cause liver-related morbidity and mortality, NAFLD is also associated with subclinical and clinical cardiovascular disease (CVD). Growing evidence indicates that patients with NAFLD are at substantial risk for the development of hypertension, coronary heart disease, cardiomyopathy, and cardiac arrhythmias, which clinically result in increased cardiovascular morbidity and mortality. The natural history of NAFLD is variable and the vast majority of patients will not progress from simple steatosis to fibrosis and end stage liver disease. However, patients with progressive forms of NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, as well as NAFLD patients with concomitant types 2 diabetes are at highest risk for CVD. This review describes the underlying pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a metabolic dysfunction associated cardiovascular risk factor, and focuses on common cardiovascular manifestations in NAFLD patients.

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

Multiple dietary patterns have been associated with different diseases; however, their comparability to improve overall health has yet to be determined. Here, in 205,776 healthcare professionals from three US cohorts followed for up to 32 years, we prospectively assessed two mechanism-based diets and six diets based on dietary recommendations in relation to major chronic disease, defined as a composite outcome of incident major cardiovascular disease (CVD), type 2 diabetes and cancer. We demonstrated that adherence to a healthy diet was generally associated with a lower risk of major chronic disease (hazard ratio (HR) comparing the 90th with the 10th percentile of dietary pattern scores = 0.68–0.84). Participants with low insulinemic (HR = 0.68, 95% confidence interval (CI) = 0.67, 0.70), low inflammatory (HR = 0.70, 95% CI = 0.69, 0.72) or diabetes risk-reducing (HR = 0.77, 95% CI = 0.75, 0.79) diet had the largest risk reduction for incident major CVD, type 2 diabetes and cancer as a composite and individually. Similar findings were observed across gender and diverse ethnic groups. Our results suggest that dietary patterns associated with markers of hyperinsulinemia and inflammation and diabetes development may inform on future dietary guidelines for chronic disease prevention. Analyses of eight dietary patterns revealed that adherence to low insulinemic, low inflammatory or diabetes risk-reducing diets was associated with the largest risk reduction of cardiometabolic diseases and cancer in US men and women.