Increased Insulin Clearance Research Articles

Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance

Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited. In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery. Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001). This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.

Sleeve Gastrectomy-Induced Weight Loss Increases Insulin Clearance in Obese Mice.

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose-insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

137-OR: A Genetic Approach to Detangling the Heterogeneity of Fasting Insulin Levels

Fasting insulin (FI) is a heterogeneous trait with high variability between individuals and populations. Increased FI is associated with an increased risk of type 2 diabetes (T2D) and its complications, including coronary artery disease (CAD) and hypertension (HTN) . We hypothesize that we could use a genetic approach to cluster FI-associated variants, characterize the clusters in terms of insulin processes within the Mexican American Cardiovascular Disease Study (MACAD; N=821) , and test for association of polygenic scores (PS) created from these clusters with T2D, CAD and HTN in three cohorts: Mass General Brigham Biobank (MGBB; N=18,127) , Aspirin in Reducing Events in the Elderly (ASPREE; N=13,349) , and Framingham Heart Study (FHS; N=7,145) . We identified six clusters using a soft clustering approach with 446 FI-increasing genetic alleles and 27 FI-related traits. Associations in two of the clusters, allowed us to characterize them and show their impact on T2D and T2D-associated complications. The first cluster had alleles associated with increased subcutaneous and visceral adiposity and was characterized by reduced insulin sensitivity (from euglycemic clamp; P=0.02) , increased insulin secretion (from oral glucose tolerance test [OGTT]; P=0.04) , and increased insulin clearance (from euglycemic clamp; P=0.02) in MACAD. This cluster’s PS was associated with HTN (MGBB Odds ratio (OR) = 1.04, P=0.013) , T2D (MGBB OR = 1.04, P =0.001) and CAD (MGB OR=1.07, P =0.008; ASPREE OR=1.04, P =0.036) The second cluster had alleles associated with a lipodystrophy phenotype and was characterized by increased insulin secretion (from OGTT P =0.019) in MACAD. We observed associations of the PS with T2D (MGBB OR= 1.13, P =2.3x10-10) and HTN (MGBB OR = 1.06, P =0.001) which were replicated in ASPREE and FHS. Our results suggest the presence of two different FI-associated genetic domains and elucidate the deleterious mechanisms by which increased FI is associated with T2D and T2D complications. Disclosure M.Sevilla: None. M.O.Goodarzi: None. D.A.Dicorpo: None. J.I.Rotter: None. J.B.Meigs: Consultant; Quest Diagnostics. M.Udler: None. A.Manning: None. Funding UM1DK078616

1460-P: Tauroursodeoxycholic Acid (tudca) Improves the Morphofunction of Pancreatic Beta Cells in Postweaning Protein-Restricted Mice

Protein restriction in the postweaning diet in mice impairs glucose metabolism by reducing insulin secretion from pancreatic β cells. TUDCA in obese rodents and humans normalized insulin secretion, increased insulin clearance, furthermore recovered mass and the number of β cells per islet in animal models of diabetes. This study aimed to evaluate the effects of TUDCA on the morphology and function of pancreatic β cells in mice subjected to postweaning protein restriction. Male C57Bl/6J mice at 30 days of age received a control diet (14% protein - group C) or a protein-restricted diet (6% protein - group R) for 16 weeks. During the last 2 weeks, 50% of the animals in each group received intraperitoneal treatment with daily doses of 300 mg/kg of body weight of TUDCA (CT and RT) , and the remainder received PBS (C and R) . The R mice that showed decreased total plasma protein and serum albumin concentration had lower weight gain and feed efficiency, but increased white adipose tissue weight. There were no differences in fasting blood glucose between the groups. The R mice that have increased insulin sensitivity after treatment with TUDCA had normalized sensitivity. Isolated islets from R mice have lower insulin secretion, which has been associated with decreased morphometric parameters compared to C. In RT mice secretion was restored in response to 2.8 mM and 11.mM glucose and the pancreas of the RT showed a greater area of β cells in relation to the area of the islets and a greater number of islets compared to R. Furthermore, RT mice showed an increase in the expression of genes of the SNARE complex, genes of function, transcription and differentiation of pancreatic β cells. We conclude that TUDCA improves glycemic homeostasis, increases insulin secretion and improves the functioning of pancreatic β cells in mice subjected to protein restriction, indicating that TUDCA can be used as a therapeutic strategy to normalize insulin secretion in protein malnutrition. Disclosure L.M.Barreto dos santos: None. T.Araujo: None. B.L.Alves: None. S.Ferreira: None. P.L.Zimath: None. J.F.Vettorazzi: None. E.M.Carneiro: None. Funding Conselho Nacional de Desenvolvimento Científico e Tecnológico (134270/2019-3)

Interaction Between Non-Insulin Glucose-Lowering Medication and Exercise in Type 2 Diabetes Mellitus - New Findings on SGLT2 Inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which block glucose reabsorption in the kidneys, represent a novel class of non-insulin glucose-lowering medication used in the pharmacological therapy of type 2 diabetes mellitus (T2DM). They became available after the introduction of incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 (DPP4) inhibitors (1). All these newer drugs have multiple effects that go beyond their glucose-lowering effect (2). It has been concluded in a meta-analysis that patients with T2DM who take SGLT2 inhibitors experience fewer major adverse cardiovascular events and show reduced all-cause mortality (3). Another meta-analysis (including data from patients with T2DM, heart failure or chronic kidney disease) demonstrates that SGLT2 inhibitor use can reduce the risk of cardiac arrhythmia (4). Yet another meta-analysis shows that SGLT2 inhibitor use can reduce blood pressure in T2DM patients (5). The beneficial effects of SGLT2 inhibitors on the cardiovascular system do not only depend on the glucose-lowering effect, but are also based on other possible mechanisms, e.g. increased natriuresis and diuresis [for an overview, see (6)]. Although it is generally accepted that regular exercise also has glucose-lowering and beneficial cardiovascular effects, the combination of non-insulin glucose-lowering medication and regular exercise does not necessarily have to have additive effects on glycemic variables and/or cardiovascular health/cardiorespiratory fitness. By contrast, it has been concluded in some studies involving insulin resistant patients who take metformin, which is often recommended as the first-line medication in T2DM, that certain exercise adaptations (improvements in insulin sensitivity, peak oxygen uptake, blood pressure, lipid profile) are not further increased or can even be attenuated through metformin use (7–11). Details on the underlying molecular mechanisms of how metformin and exercise interact and affect exercise training outcomes have yet to be determined. Among others, changes in (exercise-induced) oxidative stress and/or inflammation (with effects on post-exercise cellular signals) or in (exercise-induced) autophagy have been discussed (10, 12). It should be noted, however, that not all studies report similar or blunted adaptations for all outcomes when exercise training is combined with metformin use. In the study of Viskochil et al. (13), for example, metformin and exercise training, but not exercise alone, lowered proinsulin concentrations and increased insulin clearance in adults with prediabetes. But what about the influence of SGLT2 inhibitors on training outcomes?

Hypertension Editors' Picks: Hyperaldosteronism.

Hypertension Editors' Picks: Hyperaldosteronism.

Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals.

Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study.

We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R 2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.

Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans.

Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase-deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90-120 minutes +530.5±384.1 pmol/L, P=0.004; Δinsulin 90-120 minutes +183.0±122.6, P=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg-1·min-1·pmol-1·L; P=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism.

Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association With Insulin Clearance.

Genome-wide association studies have identified more than 450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply phenotyped Mexican Americans. A total of 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B + L-GRS) were evaluated for association with diabetes and indices of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1587 Mexican Americans. Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B + L, whereas physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among nondiabetic Mexican Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B + L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method. Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B + L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for IR may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.

Abstract P2025: Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans

Primary aldosteronism is associated with an increased risk of diabetes, but the mechanism is uncertain. We enrolled 9 patients with primary aldosteronism and assessed insulin secretion and insulin sensitivity beforte and after 3-12 months after either adrenalectomy (n-6) or medical treatment (n=3). Plasma 8AM Aldosterone ( p =0.02) and 11-deoxycorticosterone ( p =0.02) decreased after treatment, whereas cortisol was unchanged ( p =0.57). Systolic blood pressure (131.1±3.6 vs 124.3±7.7; p =0.43), serum potassium (3.7±0.1 vs 4.1±0.1 mEq/L; p =0.063), and creatinine (1.1±0.1 vs 1.2±0.1 mg/dL; p =0.35) were similar after treatment. During hyperglycemic clamps, we infused glucose to increase plasma glucose to a target of 200mg/dL ( a ). The insulin response ( b , 218.6±39.8 vs 403.1±42.0 pM insulin mean at 90-120 min, p =0.004) and L-arginine stimulated insulin response ( c) increased compared to Pre-Treatment assessment. C-peptide results were similar to insulin alterations. Comparison to control subjects matched for age, race, sex, and BMI ( Figure , gray line and area indicating mean±95%CI) indicated that insulin secretion after treatment was comparable to healthy individuals. During hyperinsulinemic-euglycemic clamps, insulin clearance (steady state insulin divided by insulin infusion rate) increased after treatment (855±68 vs 615±57 mL/min, p =0.031). Insulin sensitivity decreased after treatment (30.7±2.1 vs 18.5±1.6 M/I; p =0.016), but disposition index was unchanged (acute insulin response x M/I; p =0.81).

Grain source and chromium supplementation: Effects on health, metabolic status, and glucose-insulin kinetics in Holstein heifer calves

Carbohydrate-rich diets may increase urinary excretion of chromium (Cr) and the need to supplement the diet with Cr to meet animal requirements. The present study was performed to examine the effect of the type of grain (corn vs. barley) and Cr-methionine supplementation on health-related variables, blood levels of metabolites and hormones related to energy metabolism, and insulin sensitivity in Holstein calves. Forty-eight newborn heifers (3 d of age) were assigned randomly to 4 diets in a 2 × 2 factorial arrangement. Experimental diets were either corn-based (CBD) or barley-based (BBD) diets supplemented with 0 or 0.05 mg/kg of metabolic body weight. Chromium was provided in milk before weaning (d 3-73 of age) and in prewarmed water after weaning (d 74-94 of age). There was no interaction between the type of grain and Cr on the health-related variables and blood metabolites and hormones. Type of grain did not affect fecal score, respiration rate, and rectal temperature; however, there were tendencies for higher diarrhea occurrence (odds ratio = 1.69) and lower chance of having pneumonia (odds ratio = 0.49) in calves fed BBD versus CBD despite longer duration of diarrhea (0.54 d) and shorter days with pneumonia (0.63 d) in calves fed BBD. Calves supplemented with Cr had lower fecal score during the preweaning and overall periods and respiration rate throughout the study. Supplemental Cr decreased the duration (0.63 d) and chance of having pneumonia (odds ratio = 2.01). Calves fed BBD had lower blood levels of urea N during the postweaning period, with no changes in other blood variables between CBD and BBD. Tendencies were detected for lower blood levels of β-hydroxybutyric acid during the preweaning and overall periods and higher cortisol in Cr-supplemented calves. Chromium supplementation increased insulin clearance rate and decreased the time to half-maximal concentration and the area under the curve in BBD but not CBD calves. The calves were generally healthy, and the type of grain did not affect the health and blood variables related to energy metabolism. However, Cr supplementation increased fecal consistency, decreased respiration rate and days with pneumonia, and increased insulin sensitivity when added to BBD.

Three days of a eucaloric, low-carbohydrate/high-fat diet increases insulin clearance in healthy non-obese Japanese men

Metabolic clearance rate of insulin (MCRI) is thought to help maintain glucose homeostasis even in healthy subjects. However, the effect of a low carbohydrate/high fat (LCHF) diet on MCRI in healthy subject remains unclear. To investigate the effect of a 3-day eucaloric LCHF diet on MCRI in healthy subjects, we studied 42 healthy non-obese Japanese men. Each subject consumed a eucaloric LCHF diet for 3 days. Before and after the LCHF diet, intramyocellular lipid (IMCL) levels were measured using 1H-magnetic resonance spectroscopy, and glucose infusion rate (GIR) and MCRI were evaluated with a euglycemic hyperinsulinemic clamp. The LCHF diet increased MCRI by 10% and decreased steady state serum insulin (SSSI) and GIR during glucose clamp by 10% and 6%, respectively. To further investigate the role of MCRI, we divided subjects into high-responder (HR) and low-responder (LR) groups based on the median %change in MCRI. The LCHF diet increased IMCL and decreased SSSI during glucose clamp in the HR group, while those were not altered in the LR group. Our results suggested that a 3-day eucaloric LCHF diet increases MCRI in healthy non-obese Japanese men. This change seemed to be beneficial in terms of maintaining euglycemia during low carbohydrate availability.

Beta-cell sensitivity to insulinotropic gut hormones is reduced after gastric bypass surgery

ObjectivePostprandial hyperinsulinaemia after Roux-en Y gastric bypass (GB) has been attributed to rapid nutrient flux from the gut, and an enhanced incretin effect. However, it is unclear whether surgery changes...

Elevated Insulin Clearance Contributes to the Reduced Peripheral Insulin Concentration Observed in Obese Young Asian with Type 2 Diabetes

Introduction: The importance of insulin clearance (CLins) on insulin dynamics and the role exerted in controlling glucose in type 2 subjects has recently been appreciated. Moreover, evidence in mice showed that CLins is reduced by incretin hormones at physiological levels. Aim: To evaluate in 29 young (19±1 years) multi-ethnic Asian type 2 subjects (T2D) the contribution of CLins to insulin dynamics and if an association exists with GLP-1. Methods: T2D (15F/14M; BMI=30.2±0.9 kg/m2; HbA1c=8.8±0.4% [73±4.4 mmol/mol]; mean duration of disease 2.5 years) had fasting glucose Gb=192±14 mg/mL and insulin Ib=19±3 µU/mL. They were compared to 17 (8F/9M) age-matched nondiabetic overweight (BMI=27.8±1.0, p=0.1) control subjects (CT, Gb=82±1, p<0.0001; Ib=12±2, p=0.09). All underwent a 75g 2h OGTT with measurements of glucose, insulin, C-peptide and GLP-1. Insulin secretion (ISR) was assessed by deconvolution from peripheral C-peptide; CLins) by ISR/AUCinsulin; beta cell function (BCF) by AUCC-peptide/AUCglucose; insulin sensitivity by OGIS model. GLP-1 effect on BCF (GLPE) was empirically calculated as BCF/AUCGLP-1. Results: T2D were insulin resistant (OGIS=277±16 mL/min m2 vs. 424±14) and had low BCF (82±11 pmolC-peptide/mmolglucose vs. 123±10), both p<0.0001. Lower total AUCinsulin was observed in T2D (4.7±0.7 U/L 2h vs. 11.0±1.4, p<0.0001), with higher CLins (2.06±0.19 L/min) than in CT (1.46±0.10, p=0.023). CLins directly correlated with OGIS in CT (R=0.55, p=0.02), but not in T2D (p=0.98). Despite no difference was observed in AUCGLP-1 (1.6±0.1 nmol/L 2h vs. 1.7±0.1 in CT, p=0.63), which did not correlate with CLins (p>0.2), GLPE was lower in T2D (6.2±0.9 vs. 23.4±2.3, p<0.0001). Conclusion: Reduced peripheral insulin availability in obese young Asian T2D is due not only to a markedly impaired beta cell function and reduced GLP-1 effect, but also to an increased insulin clearance, which however shows no association to GLP-1 response. Disclosure G. Pacini: None. A. Tura: None. C. Hor: None. S. Lim: None. F. Tan: None. C. Tong: None. J.Y.H. Hong: None. F. Md Zain: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. W. Mohamud: None. T. Yeow: None.

Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors.

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10-3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10-3 l/min in DIRKO mice vs. 0.54 ± 0.03 10-3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

Three Days Low-carbohydrate/High-fat Diet Increases Insulin Clearance in Non-obese Healthy Men

Three Days Low-carbohydrate/High-fat Diet Increases Insulin Clearance in Non-obese Healthy Men

Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice

Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described. However, the possible role of TUDCA in insulin clearance had not yet been explored. Here, we demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. TUDCA also increased IDE expression in human hepatic cell line HepG2. This effect was not observed in the presence of an inhibitor of the hepatic membrane bile acid receptor, S1PR2, nor when its downstream proteins were inhibited, including IR, PI3K and Akt. These results indicate that treatment with TUDCA may be helpful to counteract obesity-induced hyperinsulinemia through increasing insulin clearance, likely through enhanced liver IDE expression in a mechanism dependent on S1PR2-Insulin pathway activation.

Exercise training and metformin, but not exercise training alone, decreases insulin production and increases insulin clearance in adults with prediabetes.

Adding metformin to exercise does not augment the effect of training alone to boost whole body insulin sensitivity and lower circulating insulin concentrations. Although lower insulin concentrations (lower supply) following lifestyle and/or pharmacological interventions are primarily attributed to reductions in insulin secretion that match increases in peripheral insulin sensitivity (lower demand), it is unclear whether exercise and/or metformin exert direct effects on insulin production, extraction, or clearance. Thirty-six middle-aged, obese, sedentary adults with prediabetes were randomized to placebo (P), metformin (M), exercise and placebo (E+P), or exercise and metformin (E+M) for 12 wk. Fasting plasma proinsulin (an indicator of insulin production), C-peptide, insulin, and glucose were collected before and after the intervention. Peripheral insulin sensitivity (euglycemic clamp), hepatic insulin extraction, insulin clearance, body weight, and cardiorespiratory fitness were also measured. Fasting proinsulin was unchanged following P (19.4 ± 10.1 vs. 22.6 ± 15.0 pmol/l), E+P (15.1 ± 7.4 vs. 15.5 ± 7.4 pmol/l), or M (24.8 ± 18.9 vs. 16.7 ± 20.3 pmol/l) but was significantly reduced after E+M (18.6 ± 11.9 vs. 13.9 ± 6.7 pmol/l; P = 0.04). Insulin clearance was significantly greater following M (384.6 ± 19.4 vs. 477.4 ± 49.9; P = 0.03) and E+M (400.1 ± 32.0 vs. 482.9 ± 33.9; P = 0.02) but was unchanged in P or E+P. In this study, metformin combined with exercise training reduced circulating proinsulin, and both groups taking metformin increased insulin clearance. This suggests that adding metformin to exercise may augment or attenuate training effects depending on the outcome or organ system being assessed.NEW & NOTEWORTHY Exercise is increasingly viewed as medication, creating a need to understand its interactions with other common medications. Research suggests metformin, a widely prescribed diabetes medication, may diminish the benefits of exercise when used in combination. In this study, however, metformin combined with exercise training, but not exercise alone, lowered proinsulin concentrations and increased insulin clearance in adults with prediabetes. This may directly influence personalized prescriptions of lifestyle and/or pharmacology to reduce diabetes risk.

COMBINED TREATMENT WITH SAXAGLIPTIN PLUS DAPAGLIFLOZIN REDUCES INSULIN LEVELS BY INCREASED INSULIN CLEARANCE AND IMPROVES β-CELL FUNCTION

To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on β-cell function. Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and β-cell function was evaluated by Homeostasis Model Assessment 2. At 24 weeks, compared with baseline, saxagliptin + dapagliflozin and saxagliptin + placebo increased mean (95% confidence interval [CI]) C-peptide area under the curve (AUC0-180 min) (40.2 [9.2 to 71.3] ng/mL and 95.4 [63.4 to 127.4] ng/mL, respectively); no change was noted with dapagliflozin + placebo (14.5 [-17.6 to 46.8] ng/mL). Insulin AUC was reduced from baseline with saxagliptin + dapagliflozin (-1,120.4 [-1,633.9 to -606.9] μU/mL) and dapagliflozin + placebo (-1,018.6 [-1550.5 to -486.8] μU/mL) but increased with saxagliptin + placebo (661.2 [131.1 to 1,191.3] μU/mL). C-peptide to insulin ratio did not change versus baseline with saxagliptin + placebo but increased after saxagliptin + dapagliflozin and dapagliflozin + placebo, largely due to decreased insulin AUC with dapagliflozin. All treatments improved β-cell function (mean change [95% CI] from baseline, saxagliptin+dapagliflozin: 20.6% [16.5% to 24.8%]; dapagliflozin + placebo: 17.0% [12.7% to 21.4%]; saxagliptin + placebo: 11.0% [6.6% to 15.5%]). Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved β-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo. A1c = glycated hemoglobin AUC0-180 min = area under the curve from 0 to 180 minutes HOMA-2β = homeostasis model assessment-2 β-cell function SGLT-2 = sodium-glucose cotransporter-2 T2D = type 2 diabetes.