How does exposure to overnutrition in utero lead to childhood adiposity? Testing the insulin hypersecretion hypothesis in the EPOCH cohort.

AIMS/HYPOTHESIS: Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children. METHODS: We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up. RESULTS: >All participants were normal weight at baseline (BMIZ -0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm2), VAT (2.0 [95% CI 0.1, 3.8] mm2), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD). CONCLUSIONS/INTERPRETATION: Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia.

Hyperinsulinemia negatively affects the association between insulin resistance and blood pressure.

BACKGROUND AND AIMS: Although hyperinsulinemia and insulin resistance (IR) together cause metabolic diseases, the available evidence fails to link hyperinsulinemia with blood pressure (BP) elevation. To further understand the role of hyperinsulinemia in the pathophysiology of hypertension, we conducted this study to investigate the moderating effect of fasting insulin (FINS) on the association between IR and BP. METHODS AND RESULTS: The health screening data of 72,076 individuals were analyzed for this moderation analysis. IR was indicated by the homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride-glucose index (TyG), and triglyceride to high-density lipoprotein cholesterol ratio (TG/HDLc). In the adjusted model, three IR indicators were considered independent variables; FINS was used as a moderator, and systolic BP (SBP) and diastolic BP (DBP) were used as dependent variables. The regression coefficient of the interaction term between the three IR indicators and FINS was significantly negative in all moderation models. Simple slope tests and the Johnson-Neymann technique also indicated that FINS negatively moderated the association between IR and BP. CONCLUSIONS: This moderation analysis showed that FINS negatively mediated the association between IR and BP, suggesting that hyperinsulinemia may buffer, not reinforce, the effect of IR on hypertension.

Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis.

AIMS/HYPOTHESIS: Islet vascular fibrosis may play an important role in the progression of type 2 diabetes, but there are no mouse models allowing detailed mechanistic studies to understand how a dysfunctional islet microvasculature contributes to diabetes pathogenesis. Here we report that the transgenic AktTg mouse, unlike other mouse strains, shows an increased deposition of extracellular matrix (ECM) proteins in perivascular regions, allowing us to study the cellular mechanisms that lead to islet vascular fibrosis. METHODS: Using immunohistochemistry, we labelled the islet microvasculature and ECM in pancreas sections of AktTg mice and human donors and performed lineage tracing to follow the fate of islet pericytes. We compared islet microvascular responses in living pancreas slices from wild-type and AktTg mice. RESULTS: We found that vascular pericytes proliferate extensively, convert into profibrotic myofibroblasts and substantially contribute to vascular fibrosis in the AktTg mouse model. The increased deposition of collagen I, fibronectin and periostin within the islet is associated with diminished islet perfusion as well as impaired capillary responses to noradrenaline (norepinephrine) and to high glucose in living pancreas slices. CONCLUSIONS/INTERPRETATION: Our study thus illustrates how the AktTg mouse serves to elucidate a cellular mechanism in the development of islet vascular fibrosis, namely a change in pericyte phenotype that leads to vascular dysfunction. Because beta cells in the AktTg mouse are more numerous and larger, and secrete more insulin, in future studies we will test the role beta cell secretory products play in determining the phenotype of pericytes and other cells residing in the islet microenvironment under physiological and pathophysiological conditions. Graphical abstract.

Type 2 diabetes: one disease, many pathways.

Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin-dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.

Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver.

The effect of chronic of hyperinsulinemia in the fetal liver is poorly understood. Here, we produced hyperinsulinemia with euglycemia for ∼8 days in fetal sheep [hyperinsulinemic (INS)] at 0.9 gestation. INS fetuses had increased insulin and decreased oxygen and amino acid (AA) concentrations compared with saline-infused fetuses [control (CON)]. Glucose (whole body) utilization rates were increased, as expected, in INS fetuses. In the liver, however, there were few differences in genes and metabolites related to glucose and lipid metabolism and no activation of insulin signaling proteins (Akt and mTOR). There was increased p-AMPK activation and decreased mitochondrial mass (PGC1A expression, mitochondrial DNA content) in INS livers. Using an unbiased multivariate analysis with 162 metabolites, we identified effects on AA and one-carbon metabolism in the INS liver. Expression of the transaminase BCAT2 and glutaminase genes GLS1 and GLS2 was decreased, supporting decreased AA utilization. We further evaluated the roles of hyperinsulinemia and hypoxemia, both present in INS fetuses, on outcomes in the liver. Expression of PGC1A correlated only with hyperinsulinemia, p-AMPK correlated only with hypoxemia, and other genes and metabolites correlated with both hyperinsulinemia and hypoxemia. In fetal hepatocytes, acute treatment with insulin activated p-Akt and decreased PGC1A, whereas hypoxia activated p-AMPK. Overall, chronic hyperinsulinemia produced greater effects on amino acid metabolism compared with glucose and lipid metabolism and a novel effect on one-carbon metabolism in the fetal liver. These hepatic metabolic responses may result from the downregulation of insulin signaling and antagonistic effects of hypoxemia-induced AMPK activation that develop with chronic hyperinsulinemia.

Sympathetically mediated increases in cardiac output, not restraint of peripheral vasodilation, contribute to blood pressure maintenance during hyperinsulinemia.

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Hyperinsulinemia does not cause de novo capillary recruitment in rat skeletal muscle.

OBJECTIVE: The effect of insulin on blood flow distribution within muscle microvasculature has been suggested to be important for glucose metabolism. However, the "capillary recruitment" hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods. METHODS: We studied how hyperinsulinemia effects capillary blood flow in rat extensor digitorum longus (EDL) muscle during euglycemic hyperinsulinemic clamp using intravital video microscopy (IVVM). Additionally, we modeled blood flow and microbubble distribution within the vascular tree under conditions observed during euglycemic hyperinsulinemic clamp experiments. RESULTS: Euglycemic hyperinsulinemia caused an increase in erythrocyte (80 ± 25%, P < .01) and plasma (53 ± 12%, P < .01) flow in rat EDL microvasculature. We found no evidence of de novo capillary recruitment within, or among, capillary networks supplied by different terminal arterioles; however, erythrocyte flow became slightly more homogenous. Our computational model predicts that a decrease in asymmetry at arteriolar bifurcations causes redistribution of microbubble flow among capillaries already perfused with erythrocytes and plasma, resulting in 25% more microbubbles flowing through capillaries. CONCLUSIONS: Our model suggests increase in CEU signal during hyperinsulinemia reflects a redistribution of arteriolar flow and not de novo capillary recruitment. IVVM experiments support this prediction showing increases in erythrocyte and plasma flow and not capillary recruitment.

Aerobic exercise offsets endothelial dysfunction induced by repetitive consumption of sugar-sweetened beverages in young healthy men.

Consumption of a single, sugar-sweetened beverage (SSB) impairs vascular endothelial function. Regular aerobic exercise improves endothelium-dependent vasodilation; however, it is unknown whether these beneficial effects persist with frequent SSB consumption. Therefore, the purpose of this study was twofold; we studied the effects of repetitive SSB consumption (75 g d-glucose, 3 times/day) for 1 wk (Glu, n = 13, 23 ± 4 yr, 23.5 ± 3.4 kg/m2) on endothelium-dependent vasodilation (FMD). Then, in a separate cohort, we investigated whether 45 min of moderate-intensity aerobic exercise on five separate days offset the hypothesized decrease in FMD during the Glu protocol (Glu+Ex, n = 11, 21 ± 3 yr, 23.8 ± 2.4 kg/m2). Baseline, fasting [glucose] (P = 0.15), [insulin] (P = 0.25), %FMD (P = 0.48), absolute FMD (P = 0.66), and shear rate area under the curve (SRAUC; P = 0.82) were similar between groups. Following the interventions, fasting [glucose] (Glu: 94 ± 6 to 92 ± 6 mg/dL, Glu+Ex: 89 ± 8 to 87 ± 6 mg/dL, P = 0.74) and [insulin] (Glu: 11.3 ± 6.2 to 11.8 ± 8.9 µU/mL, Glu+Ex: 8.7 ± 2.9 to 9.4 ± 3.2 µU/mL, P = 0.89) were unchanged. %FMD was reduced in Glu (6.1 ± 2.2 to 5.1 ± 1.3%) and increased in Glu+Ex (6.6 ± 2.2 to 7.8 ± 2.4%, P < 0.05 for both). SRAUC increased similarly in both Glu [17,715 ± 8,275 to 22,922 ± 4,808 arbitrary units (A.U.)] and Glu+Ex (18,216 ± 4,516 to 21,666 ± 5,392 A.U., main effect of time P < 0.05). When %FMD was adjusted for SRAUC, attenuation was observed in Glu (0.41 ± 0.18 to 0.23 ± 0.08%/s × 103, P < 0.05) but not Glu+Ex (0.38 ± 0.14 to 0.38 ± 0.13%/s × 103, P = 0.88). Despite unchanged fasting [glucose] and [insulin], repeated consumption of SSBs impaired conduit artery vascular endothelial function. Additionally, subjects who engaged in regular moderate-intensity aerobic exercise did not demonstrate the same SSB-induced endothelial dysfunction. Collectively, these data suggest aerobic exercise may offset the deleterious effects of repetitive SSB consumption.

Postprandial microvascular blood flow in skeletal muscle: Similarities and disparities to the hyperinsulinaemic-euglycaemic clamp.

Skeletal muscle contributes to ~40% of total body mass and has numerous important mechanical and metabolic roles in the body. Skeletal muscle is a major site for glucose disposal following a meal. Consequently, skeletal muscle plays an important role in postprandial blood glucose homeostasis. Over the past number of decades, research has demonstrated that insulin has an important role in vasodilating the vasculature in skeletal muscle in response to an insulin infusion (hyperinsulinaemic-euglycaemic clamp) or following the ingestion of a meal. This vascular action of insulin is pivotal for glucose disposal in skeletal muscle, as insulin-stimulated vasodilation increases the delivery of both glucose and insulin to the myocyte. Notably, in insulin-resistant states such as obesity and type 2 diabetes, this vascular response of insulin in skeletal muscle is significantly impaired. Whereas the majority of work in this field has focussed on the action of insulin alone on skeletal muscle microvascular blood flow and myocyte glucose metabolism, there is less understanding of how the consumption of a meal may affect skeletal muscle blood flow. This is in part due to complex variations in glucose and insulin dynamics that occurs postprandially-with changes in humoral concentrations of glucose, insulin, amino acids, gut and pancreatic peptides-compared to the hyperinsulinaemic-euglycaemic clamp. This review will address the emerging body of evidence to suggest that postprandial blood flow responses in skeletal muscle may be a function of the nutritional composition of a meal.

Metformin metabolic and vascular effects in normal weight hyperinsulinemic polycystic ovary syndrome patients treated with contraceptive vaginal ring. A pilot study.

PURPOSE: The aim of this longitudinal, controlled, and retrospective pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, and surrogate markers of arterial function in normal weight polycystic ovary syndrome patients. MATERIAL AND METHODS: Among 28 lean patients, 15 were treated with vaginal ring plus metformin and 13 women with only vaginal ring. The effects were assessed after six months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; and oral glucose tolerance test. RESULTS: After six months, the fasting insulin, glucose/insulin ratio, and homeostatic model assessment estimates for insulin resistance were significantly improved in metformin group. The ophthalmic artery pulsatility index did not significantly improve in either group. The brachial artery vasodilation was better in metformin treated patients. CONCLUSION: Metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of a slight possible cardiovascular and cerebrovascular protective effect.

Hyperinsulinemia rather than insulin resistance itself induces blood pressure elevation in high fat diet-fed rats.

OBJECTIVE: To investigate if insulin resistance per se or the accompanying hyperinsulinemia induced hypertension and its underlying mechanisms. METHODS: Sprague-Dawley rats were randomized into normal diet-fed group (ND group) and high-fat diet-fed group (HFD group). Then, the HFD group was further randomly divided into the control group (HFD_C group), the PIO group (treated with pioglitazone), the STZ_DM group (to induce diabetes with streptozotocin) and the DM+Ins group (streptozotocin injection followed by insulin treatment). Insulin sensitivity, plasma insulin, endothelin-1, norepinephrine, aldosterone, angiotensinⅡ and 24-h urinary sodium excretion (USE) levels of the groups were measured and analyzed. A multiple stepwise regression analysis method was applied to exam our hypothesis. RESULTS: Compared to HFD_C group, the groups with lower plasma insulin, the PIO group and STZ_DM group, showed higher USE and lower blood pressure. The groups with higher plasma insulin (but same level of insulin resistance), the HFD_C group and DM+Ins group, showed lower USE and higher blood pressure. The 24-h urinary sodium excretion was the most important contributor to the significant changes of blood pressure with an R2 of 25.2% in this animal experiment. CONCLUSIONS: It is the compensatory hyperinsulinemia rather than insulin resistance per se that causes blood pressure elevation. The urinary sodium excretion is the key mediator among the multiple mechanisms. Therapies targeting hyperinsulinemia and restricting salt intake may favor a better control of hypertension associated with insulin resistance.

Impaired Endothelium-Dependent Hyperpolarization Underlies Endothelial Dysfunction during Early Metabolic Challenge: Increased ROS Generation and Possible Interference with NO Function.

Endothelial dysfunction is a hallmark of diabetic vasculopathies. Although hyperglycemia is believed to be the culprit causing endothelial damage, the mechanism underlying early endothelial insult in prediabetes remains obscure. We used a nonobese high-calorie (HC)-fed rat model with hyperinsulinemia, hypercholesterolemia, and delayed development of hyperglycemia to unravel this mechanism. Compared with aortic rings from control rats, HC-fed rat rings displayed attenuated acetylcholine-mediated relaxation. While sensitive to nitric oxide synthase (NOS) inhibition, aortic relaxation in HC-rat tissues was not affected by blocking the inward-rectifier potassium (Kir) channels using BaCl2 Although Kir channel expression was reduced in HC-rat aorta, Kir expression, endothelium-dependent relaxation, and the BaCl2-sensitive component improved in HC rats treated with atorvastatin to reduce serum cholesterol. Remarkably, HC tissues demonstrated increased reactive species (ROS) in smooth muscle cells, which was reversed in rats receiving atorvastatin. In vitro ROS reduction, with superoxide dismutase, improved endothelium-dependent relaxation in HC-rat tissues. Significantly, connexin-43 expression increased in HC aortic tissues, possibly allowing ROS movement into the endothelium and reduction of eNOS activity. In this context, gap junction blockade with 18-ß-glycyrrhetinic acid reduced vascular tone in HC rat tissues but not in controls. This reduction was sensitive to NOS inhibition and SOD treatment, possibly as an outcome of reduced ROS influence, and emerged in BaCl2-treated control tissues. In conclusion, our results suggest that early metabolic challenge leads to reduced Kir-mediated endothelium-dependent hyperpolarization, increased vascular ROS potentially impairing NO synthesis and highlight these channels as a possible target for early intervention with vascular dysfunction in metabolic disease. SIGNIFICANCE STATEMENT: The present study examines early endothelial dysfunction in metabolic disease. Our results suggest that reduced inward-rectifier potassium channel function underlies a defective endothelium-mediated relaxation possibly through alteration of nitric oxide synthase activity. This study provides a possible mechanism for the augmentation of relatively small changes in one endothelium-mediated relaxation pathway to affect overall endothelial response and highlights the potential role of inward-rectifier potassium channel function as a therapeutic target to treat vascular dysfunction early in the course of metabolic disease.

Effect of hyperinsulinaemia and insulin resistance on endocrine, metabolic and fertility outcomes in women with polycystic ovary syndrome undergoing ovulation induction.

OBJECTIVE: The aim of this study was to evaluate the effects of hyperinsulinaemia and insulin resistance (IR) on reproductive and metabolic disorders and fertility in women with polycystic ovary syndrome (PCOS). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: This was a multicenter, randomized controlled trial involving a total of 1000 women diagnosed with PCOS according to the modified Rotterdam criteria at 21 sites (27 hospitals). We evaluated the effects of serum insulin levels and HOMA-IR on parameters and outcomes. The main outcome measures were anthropometric, biometric and ultrasound parameters at baseline and the clinical outcomes of ovulation, conception, pregnancy, live birth and pregnancy loss. RESULTS: The relevant analysis between hyperinsulinaemia and IR and clinical characteristics showed that weight, waist and hip circumference, BMI, waist-to-hip ratio, acanthosis nigricans score and menstrual period were significantly correlated with fasting insulin (FIN) and HOMA-IR. There was no significant correlation between the hirsutism score or acne score with FIN or HOMA-IR. The relevant analysis between hyperinsulinaemia and IR and circulating sex steroids and gonadotrophins showed that FAI was significantly correlated with FIN and HOMA-IR (r = 0.240, P < 0.001 and r = 0.191, P < 0.001, respectively). Free testosterone was significantly correlated with FIN after adjusting for the influence of age. LH and LH/FSH were not related to FIN or HOMA-IR after statistical correction for differences in BMI. The relevant analysis between hyperinsulinaemia and IR and metabolic profile showed that FIN and HOMA-IR were positively associated with fasting glucose, cholesterol, triglycerides, low-density lipoprotein, Apo B, and the incidence of metabolic syndrome and were negatively associated with high-density lipoprotein. The predictive analysis between hyperinsulinaemia and IR with fertility showed that the levels of FIN and HOMA-IR were related to the fertility outcome (ovulation, pregnancy, conception or live birth) in patients with PCOS. After adjustments for age, total testosterone and free testosterone, increasing serum insulin levels and HOMA-IR were significantly associated with decreased cycle ovulation, conception, pregnancy and live birth rates. CONCLUSIONS: Hyperinsulinaemia and IR are associated with reproductive and metabolic disorders and can predict the fertility outcomes in PCOS patients.

Temporal relationship between body mass index and triglyceride-glucose index and its impact on the incident of hypertension.

BACKGROUND AND AIMS: Obesity and insulin levels can influence each other by metabolism. However, their temporal sequences and influence on hypertension are generally unknown, especially in Chinese adults. Recently, some scholars have proposed that triglycerides-glucose index (TyG) is an important indicator of insulin resistance. The study aims to describe the relationship between body mass index (BMI) and TyG index and its impact on hypertension. METHODS AND RESULTS: A total of 4081 adults (56.33% women) without antihypertensive, hypoglycemic or lipid-lowering medications were selected for the present study. Measurements of BMI and TyG index were obtained twice from 2012 to 2017. Cross-lagged panel analysis was used to describe the temporal sequences between BMI and TyG index, and the effect of their temporal relationship patterns on hypertension was explored through mediation analysis. After adjusting for confounding factors (age, sex, ethnicity et al.), the cross-lagged path coefficient from baseline BMI to follow-up TyG (ρ2 = 0.135, P < 0.001) was significantly greater than the path coefficient from baseline TyG to follow-up BMI (ρ1 = 0.043, P < 0.001), and P < 0.001 for the difference between ρ1 and ρ2. Furthermore, the sensitivity analyses between women and men revealed identical findings. In addition, TyG index mediation effect on BMI-hypertension was estimated to be 38.45% (P < 0.001) in total population, 25.24% in women and 57.35% in men. CONCLUSION: These results provided evidence that the temporal relationship between BMI and insulin resistance is reciprocal and a higher BMI precedes hyperinsulinemia in Chinese adults. This relationship plays an essential role in the development of hypertension, while there is a difference between women and men.

Anti-diabetic effect of S-adenosylmethionine and α-glycerophosphocholine in KK-Ay mice.

Six-week-old male KK-Ay mice received drinking water with S-adenosylmethionine (SAM), α-glycerophosphocholine (GPC), or SAM+GPC for 10 weeks. The serum glucose of SAM+GPC at 15 weeks old, total cholesterol of GPC at 12 weeks old, and triglyceride of GPC at 15 weeks old and of SAM at 16 weeks old were reduced. SAM+GPC reduced serum leptin and food intake. Abbreviations: SAM: S-adenosylmethionine; GPC: α-glycerophosphocholine.

Metformin metabolic and vascular effects in overweight/moderately obese hyperinsulinemic PCOS patients treated with contraceptive vaginal ring: a pilot study.

The aim of this pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, fat distribution, and surrogate markers of arterial function. Among 62 patients, 25 were treated with vaginal ring plus metformin and 37 women with only vaginal ring. The effects were assessed after 6 months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; extended view ultrasonographic evaluation of fat distribution; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; oral glucose tolerance test. After 6 months, the body mass index and waist/hip ratio resulted significantly better in patients who associated metformin to vaginal ring. The fasting glucose, insulin, and glucose/insulin ratio, HOMA-IR, glucose, and insulin AUC 120 were significantly improved in metformin group. The ultrasonographic fat analysis resulted significantly better after metformin. The ophthalmic artery PI significantly improved in metformin group. The brachial artery vasodilation was better in metformin treated patients. In conclusion, metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism, reduces the body weight and android fat distribution. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of possible cardiovascular and cerebrovascular protective effects.

T2DM inhibition of endothelial miR-342-3p facilitates angiogenic dysfunction via repression of FGF11 signaling.

Understanding the function and molecular relevance of distinct miRNAs in endothelial cells (ECs) paves avenues for possible therapeutic intervention by targeting epigenetic mechanisms in vascular endothelial dysfunction, one of the major complications of type 2 diabetes mellitus (T2DM). MiR-342-3p, an obesity-associated miRNA, has recently been shown to be significantly upregulated in human angiosarcoma compared to benign hemangioma, indicating its potential involvement as a proangiogenic factor. Herein, we show that endothelial miR-342-3p expression was significantly compromised in T2DM organisms and this inhibition powerfully blocked vasculogenesis in vivo by repressing endothelial proliferation and migration. From a mechanistic standpoint, miR-342-3p promoted the transactivation of fibroblast growth factor 11 (FGF11) by directly targeting its 3' untranslated regions (3'UTRs). Functionally, overexpression of exogenous FGF11 successfully rescued miR-342-3p deficiency-impaired endothelial proliferation and migration. Thus, perturbation of miR-342-3p/FGF11 cascade by hyperinsulinemia plays a causative role in the induction of vascular dysfunction in T2DM. Overall, the current study underscore an endothelial facet of miR-342-3p, which may operate as a novel epigenetic integrator linking adipogenic homeostasis and angiogenesis.

Physiological hyperinsulinemia caused by acute hyperglycemia minimizes renal sodium loss by direct action on kidneys.

This study used acute, renal artery insulin infusion in conscious rats to test the hypothesis that hyperinsulinemia attenuates glucose-induced natriuresis by a direct renal mechanism. We reported previously that hyperinsulinemia was required to prevent ad libitum eating or an acute glucose bolus from causing excessive renal sodium loss. Rats were instrumented with renal artery, aortic, and femoral vein catheters and Data Sciences International blood pressure telemeters and were housed in metabolic cages. Insulin was clamped chronically at normal levels in two groups [vehicle infused (irV) and insulin infused (irI)] by administering streptozotocin and then infusing insulin intravenously 24 h/day to maintain normal blood glucose. Bolus glucose administration was used as a meal substitute to produce hyperglycemia that was not different between groups, and urinary sodium excretion (UNaV) was measured over the next 4 h. In the irV and control (C) rats, vehicle was infused in the renal artery during that period, whereas insulin was infused in the renal artery of the irI rats. Plasma insulin increased significantly in C rats but not in either of the clamped groups. UNaV in the irV rats, which could not increase circulating insulin levels, was approximately threefold greater than in C rats, similar to our previous report. However, allowing the kidney of irI rats to experience hyperinsulinemia via the renal artery insulin infusion completely prevented this, with no blood pressure differences. These data support our hypothesis that meal-induced increases in plasma insulin are a major component of normal sodium homeostasis, and that this occurs by direct action of insulin on the kidney.

Insulin increases ventilation during euglycemia in humans.

Evidence from animal studies indicates that hyperinsulinemia, without changes in glucose, increases ventilation via a carotid body-mediated mechanism. However, whether insulin elevates ventilation in humans independently of changes in glucose remains unclear. Therefore, we tested the hypothesis that insulin increases ventilation in humans during a hyperinsulinemic-euglycemic clamp in which insulin was elevated to postprandial concentrations while glucose was maintained at fasting concentrations. First, in 16 healthy young men ( protocol 1), we retrospectively analyzed respiration rate and estimated tidal volume from a pneumobelt to calculate minute ventilation during a hyperinsulinemic-euglycemic clamp. In addition, for a direct assessment of minute ventilation during a hyperinsulinemic-euglycemic clamp, we retrospectively analyzed breath-by-breath respiration rate and tidal volume from inspired/expired gasses in an additional 23 healthy young subjects ( protocol 2). Clamp infusion elevated minute ventilation from baseline in both protocols ( protocol 1: +11.9 ± 4.6% baseline, P = 0.001; protocol 2: +9.5 ± 3.8% baseline, P = 0.020). In protocol 1, peak changes in both respiration rate (+13.9 ± 3.0% baseline, P < 0.001) and estimated tidal volume (+16.9 ± 4.1% baseline, P = 0.001) were higher than baseline during the clamp. In protocol 2, tidal volume primarily increased during the clamp (+9.7 ± 3.7% baseline, P = 0.016), as respiration rate did not change significantly (+0.2 ± 1.8% baseline, P = 0.889). Collectively, we demonstrate for the first time in humans that elevated plasma insulin increases minute ventilation independent of changes in glucose.

Ten-year weight gain is associated with elevated fasting insulin levels and precedes glucose elevation.

BACKGROUND: Numerous studies have examined the relationship between endogenous insulin and weight change with mixed results. This study examined the relationship between fasting insulin levels, insulin resistance (IR), and 10-year weight change by glycaemic stage. METHODS: Using data from the US National Health and Nutrition Examination Survey 2011-2014, 3840 participants were divided into 6 groups based on fasting glucose and fasting insulin levels. Fasting insulin concentrations were dichotomized into <25th percentile (normal) and ≥25th percentile (elevated). Ten-year weight change associated with fasting insulin was assessed by glycaemic stage. RESULTS: Average weight change over a 10-year period was higher in individuals with elevated insulin levels compared to the first quartile (1.40 lbs. vs 11.12 lbs, P < .0001). Across all groups, a 1 µU increase in fasting insulin levels resulted in a 0.52-pound increase in weight (P < .0001). Similarly, an increase in HOMA-IR was associated with increase in weight (1.32 lbs per IR unit, P < .0001). Marginal increases in weight were most pronounced in the normal insulin groups compared to elevated insulin groups and diminished as glycaemic stage progressed. CONCLUSIONS: Elevated fasting insulin level was positively associated with weight gain. The impact of fasting insulin and IR on weight gain preceded hyperglycaemia and diminished as glycaemic stage progressed.