Insulin Exposure Research Articles

Effect of Insulin on Indices of Cerebral Blood Flow and Cerebrovascular Compliance in Young Adults.

Insulin has important vasodilatory effects in the peripheral circulation, but less is known about insulin's role in cerebrovascular control. Herein, we hypothesized both systemic (intravenous) and local (intranasal) insulin administration would increase indices of cerebral blood flow and reduce cerebrovascular compliance (Ci) in young adults. Participants were assigned to one of four separate protocols. Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) and blood pressure (BP, finger photoplethysmography) were measured at baseline and1) 2 minutes of carbon dioxide (CO2) air breathing (high flow control), 2) 60 minutes of euglycemic intravenous insulin infusion (40 mU/m2 body surface area/min), 3) 60 minutes following 160 IU of intranasal insulin, 4) 60 minutes of time control. Ci was calculated (modified Windkessel model). Intravenous insulin increased serum insulin (6.0±2.6 to 52.7±12.7 μIU/mL, p<0.001), whereas serum insulin was reduced following intranasal insulin (6.9±4.5 to 4.9±1.8 μIU/mL, p=0.030). MCAv increased in response to CO2 (60±13 to 69±11 cm/s, p<0.001) but was unchanged with time control (50±7 to 49±8, p=0.658) and both insulin conditions (intravenous: 61±13 to 62±17 cm/s, p=0.531; intranasal: 57±12 to 51±15 cm/s; p=0.061). In contrast, Ci remained at baseline levels over time (p=0.438) and was reduced from baseline under CO2 and both insulin conditions (CO2, p<0.001; intravenous, p=0.021; intranasal, p=0.001). Contrary to our hypothesis, there was no effect of systemic or local insulin administration on resting MCAv in young adults; however, both systemic and local insulin administration reduced Ci. These findings advance our understanding of the cerebrovascular response to acute insulin exposure.

Duration of morning hyperinsulinemia determines hepatic glucose uptake and glycogen storage later in the day.

The second-meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 h of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, the same total amount of insulin was administered either over 2 h in the first (Ins2h-A) or second (Ins2h-B) half of the morning or over the entire 4 h (Ins4h) of the morning. In the 4-h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared with the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.NEW & NOTEWORTHY Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

In vivo mapping of postprandial hepatic glucose metabolism using dynamic magnetic resonance spectroscopy combined with stable isotope flux analysis in Roux-en-Y gastric bypass adults and non-operated controls: A case-control study.

Roux-en-Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post-bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB-operated patients with PBH compared to non-operated healthy controls (HC). We enrolled RYGB-operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6'-2H2]-glucose (d-glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post-d-glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco-regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models. In RYGB subjects, the hepatic d-glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d-glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between-group differences in peripheral insulin sensitivity. Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose-insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients.

MCM proteins are up-regulated in placentas of women with reduced insulin sensitivity.

In the first trimester of pregnancy the human placenta grows rapidly, making it sensitive to changes in the intrauterine environment. To test whether exposure to an environment in utero often associated with obesity modifies placental proteome and function, we performed untargeted proteomics (LC-MS/MS) in placentas from 19 women (gestational age 35-48 days, i.e. 5+0-6+6 weeks). Maternal clinical traits (body mass index, leptin, glucose, C-peptide and insulin sensitivity) and gestational age were recorded. DNA replication and cell cycle pathways were enriched in the proteome of placentas of women with low maternal insulin sensitivity. Driving these pathways were the minichromosome maintenance (MCM) proteins MCM2, MCM3, MCM4, MCM5, MCM6 and MCM7 (MCM-complex). These proteins are part of the pre-replicative complex and participate in DNA damage repair. Indeed, MCM6 and γH2AX (DNA-damage marker) protein levels correlated in first trimester placental tissue (r = 0.514, P<0.01). MCM6 and γH2AX co-localized to nuclei of villous cytotrophoblast cells, the proliferative cell type of the placenta, suggesting increased DNA damage in this cell type. To mimic key features of the intrauterine obesogenic environment, a first trimester trophoblast cell line, i.e., ACH-3P, was exposed to high insulin (10 nM) or low oxygen tension (2.5% O2). There was a significant correlation between MCM6 and γH2AX protein levels, but these were independent of insulin or oxygen exposure. These findings show that chronic exposure in utero to reduced maternal insulin sensitivity during early pregnancy induces changes in the early first trimester placental proteome. Pathways related to DNA replication, cell cycle and DNA damage repair appear especially sensitive to such an in utero environment.

Morning Engagement of Hepatic Insulin Receptors Improves Afternoon Hepatic Glucose Disposal and Storage.

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs indirect insulin action), it is not known if insulin's delivery route affects the second meal response. To determine whether morning peripheral insulin delivery (as occurs clinically (subcutaneous)) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered via the portal vein, or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred when insulin was delivered peripherally. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second meal phenomenon via its indirect actions on the liver, but rather through direct activation of hepatic insulin signaling.

Assessing the effects of ex vivo hormonal exposure on oxidative responses in equine leukocytes: A preliminary study

Breed differences exist between horses and ponies in circulating concentrations of several hormones, notably ACTH and insulin. These hormones regulate stress and metabolic responses, but in other species, they also impact leukocyte oxidant responses. The effects of these hormones on equine leukocytes have not been evaluated to date. If equine leukocytes are similarly regulated, breed differences in increased plasma hormone concentrations or altered sensitivity to them at the leukocyte level could result in breed-related differences in oxidant responses or oxidative status. The objective of this study was therefore to determine the effects of ex vivo exposure to adrenocorticotropic hormone (ACTH), α-melanocyte stimulating hormone (α-MSH), insulin, or leptin on reactive oxygen species (ROS) production from leukocytes isolated from horses and ponies. We hypothesized that ACTH, α-MSH, insulin, and leptin would alter oxidant responses from equine leukocytes in a breed specific manner. Blood was collected from 10 apparently healthy Quarter horses and seven Welsh ponies for isolation of neutrophils and peripheral blood mononuclear cells (PBMCs) via density gradient centrifugation. Cells were incubated with media (negative control), microbial antigens (positive control), or ACTH, α-MSH, leptin, or insulin for two hours. Induced ROS production was quantified with a previously validated fluorometric assay. Data was compared within groups by comparing a stimulant within a group (horses or ponies) to baseline, between groups by comparing horse response to pony response, and among stimulants using one- and two-way, repeated measures ANOVA (P<0.05). There was no significant effect of breed on basal, microbial-induced, or hormone-induced ROS production from neutrophils (P=0.465) or PBMCs (P=0.749), but in neutrophils, a significant interaction between breed and stimulant was present (P=0.037). ROS production from PBMCs from horses after hormone exposure did not differ from cells exposed to media only (P=0.1520–0.8180). Similarly, neither leptin nor insulin exposure significantly induced ROS production from PBMCs from ponies (P= 0.2645 and 0.4678 respectively), but exposure to ACTH or α-MSH induced a significant increase in ROS production (P=0.0441 and 0.0440 respectively) compared to unstimulated cells. Hormones that vary in availability among breeds may induce ex vivo pro-oxidant responses in equine leukocytes, but specific effects are breed-, leukocyte type-, and hormone-dependent. Breed differences in hormonally induced leukocyte ROS production may warrant further investigation in the context of circulating oxidative stress and how this might relate to future disease risk.

Duration of Morning Hyperinsulinemia Determines Hepatic Glucose Uptake and Glycogen Storage Later in the Day.

Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

Targeting cancer stress-associated hyperinsulinemia and abnormal behavior mitigates lung carcinoma in postmenopausal mouse: Intervention function of peimine

Obesity stress and its associated metabolic disruption increase the likelihood and advancement of several forms of malignancies, such as postmenopausal lung cancer in humans. Also, the mechanism of lung cancer stress-related cognitive impairment and rhythm change are still unknown. Peimine (PE), an alkaloid derived from the Fritillaria genus, has the ability to mitigate the metabolic dysfunctions induced by obesity and inhibit tumor growth. The objective of this study was to investigate the regulatory impact of PE on obese mice with postmenopausal lung cancer generated by a high fat diet. Our initial findings indicate that PE can significantly reduce the metabolic dysfunction caused by a high-fat diet in mice. This is demonstrated by better glucose tolerance and insulin resistance, reduced accumulation of lipids in the liver, and improved histological alterations in the mammary fat pad. Subsequently, the treatment of PE suppressed the formation of lung tumors caused by a high-fat diet in mice models placed in their original location. In addition, PE effectively inhibited the formation of pre-existing lung tumors in a mouse model of postmenopausal women who were fed a high-fat diet. This treatment also reduced the severity of metabolic problems. Notably, laboratory studies demonstrated that insulin exposure increased the growth and movement of lung cancer cells, but this effect was significantly reduced when the cells were co-cultured with PE. Meanwhile, PE intervention can significantly alleviate cancer stress-related cognitive impairment and disturbed circadian rhythm changes and associated gene expression abnormalities in model animals. Analysis using bioinformatics and molecular biology techniques revealed that PE has the ability to decrease the expression levels of signal transducer and activator of transcription 3 (STAT3) in the liver, mammary fat pad, and tumor tissues of postmenopausal mice with obesity generated by a high-fat diet. The inhibitory effects of PE on the growth and movement of lung cancer cells induced by insulin were completely eliminated when STAT3 expression was removed. This suggests that the suppression of STAT3 expression is crucial for PE to exert its anti-cancer effects against lung cancer in the presence of high insulin levels. The findings of our study indicate that consuming PE is highly effective in preventing and treating lung cancer that is connected with obesity. This is achieved via regulating the signaling pathway of STAT3.

P-765 Minding the sweet spot in birth weight: Metformin and insulin versus no treatment

Abstract Study question Is the use of metformin or insulin associated with an increased risk of large or small for gestational age birth in comparison to drug-naïve GDM? Summary answer No difference in SGA / LGA odds with drug-naïve mothers versus metformin-exposed, but higher odds of SGA and lover odds of LGA compared to insulin-exposed. What is known already In Europe, the originator brand of metformin has received a label update allowing the use during pregnancy. Use of metformin during pregnancy is associated with a reduced risk of LGA, but increased risk of SGA birth compared to insulin. In CLUE, metformin only exposure demonstrated a reduced odds of LGA birth (weighted OR (wOR) 0.82, 95% CI 0.67 to 0.99), but increased risk for SGA (wOR 1.65, 95% CI 1.16 to 2.34). Insulin use during a hyperglycemic pregnancy is discussed to increase birth weight. Study design, size, duration This was a follow-up study performed on our previously published population-based register data cohort study CLUE with maternal exposure to metformin, insulin or diagnosed with GDM but drug-naïve until birth. The follow-up study included 3,964 subjects in the metformin only cohort, 5,273 in the insulin only cohort and 82,675 women diagnosed with GDM but without drug treatment during the respective pregnancy (naïve cohort). Participants/materials, setting, methods The study population included singleton children born to 18-45 year old women from Finland during 2004–2016. Exclusion criteria were maternal type 1 diabetes, exposure to glucocorticoids and antidiabetic medications except metformin and insulin during the respective pregnancy. Analyses of SGA and LGA used logistic regression to estimate ORs with 95%CIs, with naïve cohort as the reference. Inverse probability of treatment weighting (IPTW) with stabilized weights based on propensity scores (PS) was used to control for confounding. Main results and the role of chance The odds of SGA birth were significantly higher in the naïve cohort (wOR 1.41, 95% CI 1.11 to 1.79) compared to those exposed to insulin, and the odds for LGA birth were significantly lower (wOR 0.72, 95% CI 0.64 to 0.82). No difference was found in the odds for SGA or LGA when the metformin cohort was compared with naïve cohort (wOR 0.97, 95% CI 0.73 to 1.27 and wOR 0.91, 95% CI 0.75 to 1.11, respectively). Limitations, reasons for caution Drug exposure was assessed on the dispensed drug only. and not intake, also prohibiting dose and treatment duration stratification. Although IPTW methods were used to account for many characteristics, the prevalence of underlying diseases differed across treatment cohorts, the naïve cohort which was defined by indication and absence of treatment. Wider implications of the findings This analysis adds to the growing evidence that insulin exposure in pregnancy may increase the risk of LGA, which is associated with increased adult obesity. Metformin did not increase the odds of SGA or LGA. Metformin may be considered a reasonable treatment during pregnancy, e.g. at risk for LGA birth. Trial registration number not applicable

Targeting SIRT3 signaling alleviates lung carcinoma progression by reducing hyperinsulinemia in postmenopausal obese mice: Protective intervention of betaxanthin

Metabolic disturbances associated with obesity increase the risk and advancement of various tumor forms, including postmenopausal lung cancer, in humans. Betaxanthin, a type of yellow-orange pigment found in certain plants, particularly in some flowers, fruits, and vegetables, can be utilized to inhibit the growth of tumors and lessen the metabolic dysfunctions brought on by obesity. However, the functional role of betaxanthin (BET) in suppressing lung cancer progression and its potential mechanisms are still not fully understood. In this study, we examined the regulation of BET in obese mice with postmenopausal lung cancer receiving a high-fat diet (HFD). Initially, we found that BET could significantly mitigate the metabolic dysfunction that a high-fat diet causes in mice. Improved histological changes in the mammary fat pad, lower hepatic lipid deposition, and improved glucose tolerance and insulin resistance demonstrated this. Following that, BET treatment inhibited the formation of lung neoplasms in in-situ cancer animal models that were stimulated by HFD. Furthermore, in a postmenopausal mouse model fed HFD, BET significantly reduced the growth of pre-existing lung tumors, as well as attenuating metabolic abnormalities. Notably, in vitro research revealed that BET co-culture significantly reduced the proliferation and migration of mouse lung cancer cells, whereas insulin exposure increased these processes. Research on animals verified that lung cancer progressed due to hyperinsulinemia; however, BET treatment might inhibit this condition in postmenopausal mice on a high-fat diet. BET could up-regulate sirtuin 3 (SIRT3) expression levels in tumor, liver, and mammary fat pad tissues in postmenopausal mice with HFD-induced obesity, according to a bioinformatic and molecular biology study. Crucially, eradicating SIRT3 expression completely eliminated BET’s inhibitory effects on insulin-stimulated cancer cell proliferation and migration. This suggests that increasing SIRT3 expression may be required for BET to perform its anti-tumor function against lung cancer in conditions of hyperinsulinemia. Our findings showed that by modifying SIRT3 signaling, BET consumption is probably effective in the prevention and treatment of obesity-related lung cancer.

Review of data on comparative pharmacokinetics, pharmacodynamics, efficacy and safety of the superfast insulin drug lispro

Diabetes mellitus remains one of the main socially significant health problems worldwide. Glycemic control plays a key role in the prevention of all complications of diabetes mellitus. One of the most important factors in the overall control of glycemia in patients with both type 1 and type 2 diabetes mellitus is postprandial glucose levels, as a leading risk factor for delayed vascular complications. Modern possibilities for controlling postprandial glycemia include the use of not only ultrashort insulin preparations, but also ultrafast action. One of the superfast insulin preparations available today is the drug Lumzhev ® (inLisFast), which contains lyspro insulin as an active ingredient. A number of studies on the comparative pharmacokinetics and pharmacodynamics of inLisFast compared with insulin lispro consistently demonstrate a shift in the pharmacokinetic and pharmacodynamic profile to the left, which indicates faster absorption, an increase in early insulin exposure and a decrease in late insulin exposure. inLisFast provides flexibility in the regulation of food intake, which can play a significant role in optimizing glycemic control and improving the quality of life of patients with diabetes.

Impact of Peripheral Versus Central Insulin on Cerebrovascular Compliance in Healthy Young Adults

Objective: Vascular compliance is an essential component of cerebral blood flow regulation. Prior work has shown cerebral vasodilation (elicited by hypercapnia) reduces cerebrovascular compliance (Ci); however, this work has yet to be translated to other vasoactive compounds. Insulin has important vasodilatory effects in the peripheral circulation, but less is known about the role of insulin in cerebrovascular control. Herein, we hypothesized both peripheral (intravenous) and central (intranasal) insulin administration would increase indices of cerebral blood flow and reduce Ci in healthy young adults. Methods: Twenty-five healthy young adults (8 female; 26±7 yrs, 25±3 kg/m2) were assigned to two separate protocols (NCT05244694, NCT05153395). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) was measured at baseline and under two study conditions: 1) at the end of a 60 min hyperinsulinemic euglycemic infusion, and 2) 60 min following 160 IU of intranasal insulin. Indices of Ci were calculated using a modified Windkessel model applied to blood pressure (finger photoplethysmography) and corresponding MCAv waveforms collected over a 5-min period (10 waveforms) at baseline and during the aforementioned insulin conditions. Results: Blood glucose remained unchanged throughout both protocols (both p&gt;0.05). MCAv was maintained over time under both insulin conditions (protocol 1: 60±13 to 62±17 cm/s, p=0.635; protocol 2: 58±9 to 53±14 cm/s, p=0.146). In contrast, Ci decreased (0.00028±0.00010 to 0.00021±0.00007 cm/s/mmHg, p=0.010) from baseline during peripheral (intravenous) insulin administration. No change in Ci (0.00049±0.00025 to 0.00040±0.00018 cm/s/mmHg, p=0.189) were observed following intranasal insulin administration. Conclusions: Contrary to our hypothesis, there was no effect of peripheral or central insulin administration on resting MCAv in healthy young adults. However, intravenous (but not intranasal) insulin reduced Ci by approximately 25% from baseline values. These findings advance our understanding of cerebrovascular control mechanisms during insulin exposure and provide the opportunity to extend this work to diseased states characterized by insulin resistance, including diabetes. CAFNR Joy of Discovery (JKL, JP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Muscle Sympathetic Action Potential Firing Patterns Following Intranasal Insulin Administration in Healthy Adults

Objective: Systemic insulin increases muscle sympathetic nervous system activity (MSNA) in healthy adults by augmenting firing frequency of medium-sized sympathetic action potentials (AP) and recruiting previously latent, larger axons. Whether these neural coding patterns are due to central or peripheral effects of insulin is unclear. We examined the impact of elevated central insulin on AP firing patterns in healthy adults. We hypothesized intranasal insulin administration, which increases central insulin levels, would increase MSNA via elevated firing frequency of APs and recruitment of previously latent, larger axons. Methods: Ten participants were assigned to time control [TC, n=6 (3M/3F)] or 160 IU of intranasal insulin [n=4 (3M/1F)] administered over 5 min. MSNA (fibular microneurography) was assessed at baseline and for 30 min following insulin administration. Sympathetic APs were identified using a matched mother wavelet and continuous wavelet transform. APs were divided into the proportion of those firing in small, medium, or large amplitude clusters. AP firing frequency, percent of APs firing within an MSNA burst (synchronous), and the probability of clusters firing more than once within an MSNA burst were identified. Data are reported as median (interquartile range). Results: MSNA burst frequency increased 15 min after intranasal insulin administration [24(20) to 31(23) bursts/min, p=0.03]. At this time, the percent of synchronous APs [72(27) to 90(24)%, p=0.02] and the probability of medium-sized AP clusters firing more than once within an MSNA burst [13(14) to 19(17)%, p=0.03] increased. No changes in MSNA burst frequency [23(14) to 25(13) bursts/min, p=0.27], percent of synchronous APs [74(15) to 75(34), p=0.48], nor firing probability of medium-sized AP clusters [6(12) to 8(7)%, p=0.97] occurred in TC. The total number of detected clusters did not change in either group (p&gt;0.05). Conclusions: Intranasal insulin increases MSNA burst frequency due to a higher percent of synchronous APs, particularly medium-sized AP clusters; however, we did not observe recruitment of latent, larger axons. These exploratory data highlight potential differences in the sympathetic response to central versus peripheral insulin exposure in healthy adults. CAFNR Joy of Discovery (JKL, JP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AM Insulinization of the Liver Is an Important Driver of PM Hepatic Glucose Uptake

Glucose tolerance is significantly improved in response to consuming a second, identical meal later in the day. It is known that physiologic (portal vein) exposure to insulin in the morning primes the liver for increased hepatic glucose uptake and glycogen storage in the afternoon. Although this phenomenon has been observed in both healthy and diabetic individuals, it has not yet been established whether or not morning peripheral insulin delivery could bring about the same response. Thus, the aim of this study was to determine how the route of morning insulin delivery impacts the liver’s ability to extract and store glucose later in the day. To explore this aim, we delivered insulin into the portal vein (Po Ins) or a leg vein (Pe Ins) in the morning (AM) and subsequently challenged conscious dogs to a hyperinsulinemic-hyperglycemic (HIHG) clamp in the afternoon (PM). We then assessed the impact that each route of AM insulin delivery had on hepatic glucose uptake (HGU), non-HGU, and glycogen storage in the PM. The insulin infusion rates used in the Po Ins group were selected to mimic the rise in endogenous insulin secretion previously observed during a 4hr AM duodenal glucose infusion (2.1 mU/kg/min [0-30 min], 2.4 mU/kg/min [30-60 min], and 1.5 mU/kg/min [60-240 min]). In efforts to expose both groups to the same amount of insulin in the periphery while creating a difference at the liver, these rates were halved in the Pe Ins group. In the PM clamp, all groups received 4x basal insulin, 2x basal glycemia, and portal glucose infusion to simulate a second meal. During the 2.5hr PM clamp, the mean HGU was 1.8-fold higher in the Po Ins group vs. the Pe Ins group (HGU of 6.28±0.62 vs. 3.49±0.31 mg/kg/min; net AUC of 827±82 vs. 474±40 mg/kg/2.5hr, p&lt;0.002), respectively, with no significant difference in non-HGU (net AUC of 819±118 mg/kg/2.5hr in Po Ins vs. 684±83 mg/kg/2.5hr in Pe Ins). Additionally, mean PM hepatic glycogen content was 47% larger in Po Ins vs. Pe Ins (23.6±1.1 vs. 12.5±1.5 mg/g liver, p&lt;0.001), respectively. When compared to a group from an earlier study that received morning saline and a HIHG clamp in the afternoon (Sal Ctrl), there was no significant difference between Pe Ins and Sal Ctrl for any parameter measured. Therefore, physiologic hepatic insulin exposure in the morning is critical for increased hepatic glucose disposition and glycogen storage later in the day. 5T32DK007563 5R01DK131082-02. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Insulin induces bioenergetic changes and alters mitochondrial dynamics in podocytes.

Diabetic nephropathy (DN) is one of the most frequent complications of diabetes. Early stages of DN are associated with hyperinsulinemia and progressive insulin resistance in insulin-sensitive cells, including podocytes. The diabetic environment induces pathological changes, especially in podocyte bioenergetics, which is tightly linked with mitochondrial dynamics. The regulatory role of insulin in mitochondrial morphology in podocytes has not been fully elucidated. Therefore, the main goal of the present study was to investigate effects of insulin on the regulation of mitochondrial dynamics and bioenergetics in human podocytes. Biochemical analyses were performed to assess oxidative phosphorylation efficiency by measuring the oxygen consumption rate (OCR) and glycolysis by measuring the extracellular acidification rate (ECAR). mRNA and protein expression were determined by real-time polymerase chain reaction and Western blot. The intracellular mitochondrial network was visualized by MitoTracker staining. All calculations were conducted using CellProfiler software. Short-term insulin exposure exerted inhibitory effects on various parameters of oxidative respiration and adenosine triphosphate production, and glycolysis flux was elevated. After a longer time of treating cells with insulin, an increase in mitochondrial size was observed, accompanied by a reduction of expression of the mitochondrial fission markers DRP1 and FIS1 and an increase in mitophagy. Overall, we identified a previously unknown role for insulin in the regulation of oxidative respiration and glycolysis and elucidated mitochondrial dynamics in human podocytes. The present results emphasize the importance of the duration of insulin stimulation for its metabolic and molecular effects, which should be considered in clinical and experimental studies of DN.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365days and > 365days). The outcome was time to incident advanced adenoma. Of the 975 eligible patients, 184 patients accumulated > 365days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice.

Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 can home in on the pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to exocytotic sites on the β-cell surface, masking the antigenic exposure of ZnT8 and insulin following glucosestimulated insulin secretion. In vivo administration of mAb43 to nonobese diabetic (NOD) mice selectively increased the proportion of regulatory T-cells (Tregs) in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation and exhibited no adverse effects during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of β-cells suppresses the immunological cascade from B-cell antigen presentation to T-cell mediated β-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.

Impact of Participant Characteristics on Clinical Outcomes with iGlarLixi in Type2 Diabetes: Post Hoc Analysis of SPARTA Japan.

The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100U/mL plus lixisenatide (iGlarLixi) once daily over 6months in Japanese people with type2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. UMIN-CTR Trials Registry, UMIN000044126; registered 10 May2021.

Neonatal outcome following metformin-treated gestational diabetes mellitus: A population-based cohort study.

Neonatal hypoglycemia is a common complication associated with gestational diabetes and therefore relevant to consider in evaluations of maternal treatment. We aimed to investigate the risk of neonatal hypoglycemia in offspring exposed to metformin treatment alone (MT) or combined with insulin (MIT) in comparison with nutrition therapy alone (NT), and insulin treatment alone (IT). In addition, we investigated MT in comparison with MIT. Secondary outcomes included neonatal anthropometrics, respiratory morbidity, hyperbilirubinemia, 5-min Apgar score, and preterm birth. This Swedish population-based cohort included 16 181 women diagnosed with gestational diabetes, and their singleton offspring born in 2019-2021. We estimated risk as adjusted odds ratio (aOR) with 95% confidence interval (CI), using individual-level, linkage register-data in multivariable logistic regression models. In the main analysis, MT was associated with a lower risk of neonatal hypoglycemia vs NT (aOR 0.85, 95% CI: 0.74-0.96), vs MIT (0.74 [0.64-0.87]), and vs IT (0.47 [0.40-0.55]), whereas MIT was associated with a similar risk of neonatal hypoglycemia vs NT (1.14 [0.99-1.30]) and with lower risk vs IT (0.63 [0.53-0.75]). However, supplemental feeding rates were lower for NT vs pharmacological treatments (p < 0.001). In post hoc subgroup analyses including only exclusively breastfed offspring, the risk of neonatal hypoglycemia was modified and similar among MT and NT, and higher in MIT vs NT. Insulin exposure, alone or combined with metformin, was associated with increased risk of being large for gestational age. Compared with NT, exposure to any pharmacological treatment was associated with significantly lower risk of 5-min Apgar score < 4. All other secondary outcomes were comparable among the treatment categories. The risk of neonatal hypoglycemia appears to be comparable among offspring exposed to single metformin treatment and nutrition therapy alone, and the lower risk that we observed in favor of metformin is probably explained by a difference in supplemental feeding practices rather than metformin per se. By contrast, the lower risk favoring metformin exposure over insulin exposure was not explained by supplemental feeding. However, further investigations are required to determine whether the difference is an effect of metformin per se or mediated by other external factors.

Fetal death and abortion after in utero insulin exposure

Fetal death and abortion after in utero insulin exposure