Metabolic Clearance Rate Of Insulin Research Articles

133-OR: Insulin Dynamics across the Glucose Tolerance Spectrum in Youth with Obesity

Despite β-cell failure in youth with dysglycemia (DYSG) (IGT + T2D), fasting insulin concentrations are elevated. Here, we examined 1) metabolic clearance rate of insulin (MCRI) in youth with normal glucose tolerance (NGT) and DYSG, 2) racial/ethnic differences in insulin dynamics and 3) physical and metabolic correlates of MCRI. In 95 Black (B) + 111 White (W) youth, age 14.4 ± 2.0 [SD] yrs., BMI 34.7 ± 6.4 kg/m2, MCRI and peripheral insulin sensitivity (PIS) were calculated from the hyperinsulinemic-euglycemic clamp, 1st-phase insulin (1stPhI) from the hyperglycemic clamp, disposition index (DI=PIS x 1stPhI), % body fat by DXA, visceral adipose tissue (VAT) by MRI. In DYSG vs NGT, MCRI was lower (261.6 ± 11.9 vs 334.1 ± 8.5 ml/m2/min, p<0.001) and fasting insulin was higher (46.9 ± 4.4 vs 32.9 ± 1.2 μU/mL, p<0.001). In B vs W youth (Image), MCRI was lower driven by DYSG. Lower PIS, lower MCRI and higher 1stPhI were characteristics of B youth with DYSG vs W with equally impaired DI. In B and W youth, positive correlates of MCRI were PIS and DI and negative correlates were fasting insulin, % body fat and VAT. In conclusion, higher fasting insulin concentrations in DYSG despite a failing β-cell could be explained by decreased MCRI. Racial/ethnic contrast in insulin dynamics differs by glycemic status and is more pronounced in DYSG manifested by lower PIS and lower MCRI in B vs W youth with no difference in β-cell function relative to insulin sensitivity. Disclosure W.Cho: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. H.M.Tfayli: Other Relationship; Novo Nordisk, Research Support; Sanofi, Novartis. S.Lee: None. S.Michaliszyn: None. J.Kim: None. S.A.Arslanian: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Consultant; Société des Produits Nestlé SA,, Other Relationship; Eli Lilly and Company, AstraZeneca, Research Support; Novo Nordisk, Eli Lilly and Company. Funding American Diabetes Association (7-08-JF-27 to S.L.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24HD01357, R01HD27503); National Center for Advancing Translational Sciences (UL1TR000005); National Center for Research

A Short-Term High-Fat Diet Worsens Insulin Sensitivity with Changes in Metabolic Parameters in Non-Obese Japanese Men.

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test.

PSUN299 GLP-1 Contribution to Insulin Secretory Response to Protein Ingestion and Insulin Kinetics Following Gastric Bypass and Sleeve Gastrectomy

Abstract Rapid passage of ingested nutrients to the gut after Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) results in hyperinsulinemia after glucose ingestion, in part due to an enhanced glucagon-like peptide-1 (GLP-1)-induced insulin secretory response (ISR) and reduced metabolic clearance rate of insulin (MCRI). The effect of endogenous GLP-1 on insulin kinetics is unknown, and so is GLP-1 contribution to insulin secretory response to non-glucose nutrient ingestion. In non-surgical subjects, protein ingestion enhances insulin secretion and reduces MCRI. We hypothesized that protein ingestion enhances GLP-1-induced ISR and alters MCRI in proportion to changes in nutrient influx after GB and SG. To test this hypothesis ISR, β-cell sensitivity to glucose (BGS), MCRI, and oral glucose insulin sensitivity (OGIS) were measured on 3 days during 50 g glucose ingestion as well as 50 g protein ingestion with and without GLP-1R antagonist, exendin (9-39) [Ex-9] infusion. Ten GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN) were enrolled. The 3 non-diabetic groups were matched for age, BMI, fat-free mass, HbA1c; surgical groups were matched for weight loss and time post-surgery. Fasting glucose, insulin, and ISR were similar among the 3 groups and among the 3 studies but fasting MCRI was greater in surgical groups than CN (p<0.05). Compared to glucose, protein ingestion led to larger BGS in 3 groups despite smaller overall ISR response (AUCISR3h) (p<0.05). Blocking GLP-1R during protein ingestion decreased AUCISR3h only in surgical subjects (p<0.05 for interaction), whereas BGS was reduced similarly in 3 groups during Ex-9 infusion (p<0.05). OGIS was smaller during protein than glucose ingestion in 3 groups (p<0.05). GLP-1R blockade did not affect insulin sensitivity. Following nutrient ingestion in parallel with increase in insulin secretion MCRI was reduced to nadir values at 40 minutes, but then gradually increased approaching premeal values at different pace among surgical and non-surgical subjects (p<0.05). The slope of MCRI: Insulin (0-40 min) was smaller after protein ingestion than glucose, and after protein with Ex-9 infusion than without in 3 groups (p<0.05). Blocking GLP-1R had no effect on MCRI values in the latter phase of protein ingestion when insulin secretion reduced approaching premeal values. There was no association between parameters of insulin sensitivity and insulin clearance during glucose or protein ingestion. Our findings indicate that the regulation of insulin secretion and clearance during protein ingestion is altered after GB and SG. Further, endogenous GLP-1 contribution to insulin secretory response to protein ingestion after GB and SG is enhanced, but GLP-1 effect on insulin kinetics is trivial. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

1298-P: Metabolic Clearance of Insulin Is Altered after Gastric Bypass and Sleeve Gastrectomy

Roux-en-Y gastric bypass (GB) surgery and sleeve gastrectomy (SG) improve glucose tolerance, in part, by enhancing prandial insulin levels. Post-meal hyperinsulinemia after GB is caused by larger insulin secretion and lower metabolic clearance rate of insulin (MCRI) . Reduced prandial MCRI after GB is exaggerated in those with post-GB complication of hypoglycemia, suggesting that altered MCRI is a pathogenic factor. We investigated the role of GB or SG on insulin kinetics in fasting and fed states. The MCRI were measured during a mixed meal text (MMT) in 9 GB and 7 SG subjects: and during MMT combined with hyperinsulinemic hypoglycemic clamp in 9 GB, 7 SG, and 5 CN. Three groups were matched for age and BMI and surgical groups for time and weight loss since surgery; none had diabetes or liver disease. Fasting MCRI was greater in GB and SC than CN (p<0.05) . Meal ingestion diminished MCRI to a larger extent in GB subjects compared to SG reaching nadir values in 20-50 min (relative reduction in GB vs. SG: 82±3% vs. 74±3%, p<0.05) . The relative postprandial reduction in MCRI was inversely associated with the glycemic excursion and insulin response. During the clamp hepatic insulin clearance was larger in GB and SG compared to CN (p<0.05) . There was no association between hepatic insulin clearance and peripheral insulin sensitivity (M/I) . Induced hyperinsulinemia approximating 300 µU/ml reduced MCRI in 3 groups despite a larger M/I in surgical subjects. Meal ingestion during hyperinsulinemic hypoglycemia clamp raised MCRI in 3 groups (p<0.05) returning to pre-meal values in an hour. These findings demonstrate that the differences in basal MCRI among GB, SG and CN are mainly attributed to variations in insulin clearance in the liver and independent on peripheral insulin sensitivity. Further, prandial reduction in MCRI is greater after GB than SG in proportion to the rates of nutrient influx.; the effect of nutrient ingestion on insulin kinetics is altered during hyperinsulinemic hypoglycemia. Disclosure M.S.Rayas: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. M.Salehi: None. Funding National Institute of Diabetes, Digestive, and Kidney Diseases (DK105379)

Potential Identification of Type 2 Diabetes with Elevated Insulin Clearance

BackgroundDecreased blood insulin concentrations resulting from reduced pancreatic β-cell insulin secretion and elevated insulin clearance (IC) could be involved in impaired glucose metabolism in diabetes. Recently, we reported a patient with type 2 diabetes mellitus (T2DM) who had decreased blood insulin concentrations and elevated IC.MethodsFor this study, we recruited patients with newly diagnosed, treatment-naïve T2DM and measured the metabolic clearance rate of insulin (MCRI) determined by a hyperinsulinemic-euglycemic clamp examination. We defined elevated IC as an MCRI of more than 700 ml/min/m2. Using this tentative cutoff, we identified patients with T2DM with elevated IC and investigated their clinical characteristics.ResultsWe enrolled 101 patients in this study; 78.2% were men. Patients had a mean age of 54.1 years, a median body-mass index (BMI) of 25.1 kg/m2 (interquartile range [IQR], 22.9 to 28.4 kg/m2), a median hemoglobin A1c of 10.0% (IQR, 8.0 to 12.3%), and a median MCRI of 655 ml/min/m2 (IQR, 562 to 810 ml/min/m2). Our case definition for elevated IC was met by 44 patients whose median MCRI was 842 ml/min/m2 (IQR, 747 to 975 ml/min/m2) compared with those without elevated IC (570 ml/min/m2; IQR, 500 to 628 ml/min/m2). On the basis of this division, fasting blood glucose and insulin levels were 178 mg/dl (IQR, 140 to 218 mg/dl) and 4.2 mU/l (IQR, 2.7 to 5.5 mU/l), respectively, in patients with elevated IC compared with 146 mg/dl (IQR, 128 to 188 mg/dl) and 9.6 mU/l (IQR, 6.6 to 14.9 mU/l), respectively, in patients without elevated IC. The BMI of patients with elevated IC was 22.9 kg/m2 (IQR, 20.7 to 24.2 kg/m2) compared with 27.3 kg/m2 (IQR, 25.2 to 29.4 kg/m2) in patients who did not have elevated IC. There were no clinically significant differences in renal or hepatic function test results.ConclusionsOur data suggest that there is a group of patients with T2DM with elevated IC, and that they are nonobese and have decreased blood insulin concentrations. If confirmed, this novel form of T2DM could affect the treatment of such patients. (UMIN Clinical Trials Registry number, UMIN000032014.)

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes.

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.

Postprandial Glycemic, Insulinemic, and Short-Chain Fatty Acids Responses Following the Consumption of Okara and Biovalorized Okara Incorporated Biscuits

Abstract Objectives Okara is a fiber-rich food processing by-product. However, it is underutilized as food due to its rapid putrefaction and poor sensorial properties. Valorization via fermentation (biovalorization) can alleviate its undesirable qualities while augmenting its soluble fiber content. The increase in soluble fiber may improve postprandial glycemic and insulinemic responses, potentially via generation of short-chain fatty acids (SCFAs) from colonic bacteria fermentation. This study aimed to assess the effect of consuming okara and biovalorized okara-containing biscuits on postprandial glucose, insulin and SCFAs responses in older Singaporeans. Methods Fifteen healthy middle-aged and older Singaporeans participated in a randomized controlled crossover trial. Subjects underwent a 4-hour mixed meal tolerance test with 100 g ingestion of 3 types of biscuits – control (C, no okara), biovalorised okara (RO) and autoclaved okara (AOK). RO and AOK biscuits were produced by 20% substitution of wheat flour with okara powder that was fermented with Rhizopus oligosporus (7% w/w) or autoclaved. The 4-hour incremental area under the curve (iAUC) of glucose, insulin and SCFAs (acetate, propionate and butyrate) were assessed. β-cell function was evaluated based on glucose stimulated insulin secretion, using a ratio of 4-hour AUC of insulin to glucose. Estimated insulin sensitivity (ISI) and metabolic clearance rate (MCR) were assessed with Stumvoll Index. Results Although no difference in glucose response was noted, RO showed significantly lower insulin iAUC (RO: 8931 ± 1058 mU/L × min, mean ± SE; C: 10271 ± 866 mU/L × min, p = 0.021) and improved β-cell function (p = 0.028) compared to C. AOK yielded significantly greater ISI and MCR compared to C (pISI = 0.016, pMCR = 0.009) while RO showed no difference against AOK or C. Significantly higher acetate and total SCFAs iAUC were evident for both RO and AOK relative to C (C vs RO: pacetate = 0.012, ptotal SCFA = 0.001; C vs AOK: pacetate = 0.015, ptotal SCFA = 0.001). AOK also had significantly greater propionate and butyrate iAUC compared to C (C vs AOK: pacetate = 0.002, pbutyrate = 0.001). Conclusions Consumption of okara and biovalorized okara-containing biscuits offers the benefit of attenuating postprandial insulinemic response possibly via SCFAs modulation. Funding Sources Singapore Ministry of Education

Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans.

Impaired insulin clearance is implicated in the pathogenesis of type 2 diabetes, but prospective evidence remains limited. Therefore, we sought to identify factors associated with the metabolic clearance rate of insulin (MCRI) and to investigate whether lower MCRI is associated with increased risk of incident type 2 diabetes. From a longitudinal cohort, 570 adult Native Americans without diabetes living in the Southwestern United States were characterised at baseline and 448 participants were monitored over a median follow-up period of 7.9years with 146 (32%) incident cases of diabetes identified (fasting plasma glucose ≥7.0mmol/l, 2h plasma glucose [2-h PG] ≥11.1mmol/l, or clinical diagnosis). At baseline, participants underwent dual-energy x-ray absorptiometry or hydrodensitometry to assess body composition, a 75g OGTT, an IVGTT to assess acute insulin response (AIR), and a hyperinsulinaemic-euglycaemic clamp to assess MCRI and insulin action (M). In adjusted linear models, MCRI was inversely associated with body fat percentage (r = -0.35), fasting plasma insulin (r = -0.55) and AIR (r = -0.22), and positively associated with M (r = 0.17; all p <0.0001). In multivariable Cox proportional hazard models, lower MCRI was associated with an increased risk of diabetes after adjustment for age, sex, heritage, body fat percentage, AIR, M, fasting plasma glucose, 2-h PG, and fasting plasma insulin (HR per one-SD difference in MCRI: 0.77; 95% CI 0.61, 0.98; p =0.03). Lower MCRI is associated with an unfavourable metabolic phenotype and is associated with incident type 2 diabetes independent of established risk factors. ClinicalTrials.gov NCT00339482; NCT00340132.

Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance.

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = -0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15-30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.

Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance, and Insulin Sensitivity in Healthy Glucose-Tolerant Subjects.

The aim of the current study was to evaluate the effect of sustained physiologic increase of ∼50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH-) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h. First-phase insulin secretion (0-10 min) increased by 70%, while second-phase insulin secretion during the first (10-80 min) and second (90-160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 h of physiologic hyperglycemia. Insulin sensitivity during hyperglycemic clamp declined by ∼30% and ∼55% (both P < 0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (second clamp step) and by 62% following arginine (both P < 0.005) following 72-h glucose infusion. The effect of 72-h glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 h of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (P < 0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 h 1) increases absolute insulin secretion but impairs β-cell function, 2) causes insulin resistance, and 3) reduces metabolic clearance rate of insulin.

1864-P: Higher Relative Abundance of Bacteroidetes in Gut Microbiota Is Associated with Decreased Insulin Clearance and Insulin Sensitivity after a Short-Term High-Calorie, High-Fat Diet in Healthy Men

Hyperinsulinemia is observed in obese subject. Even in healthy non-obese subjects, intentional small weight gain by a high-calorie, high-fat diet (HCHFD) resulted in hyperinsulinemia which was caused not by increased insulin secretion but by decreased metabolic clearance rate of insulin (MCRI). In addition, it was reported that in the mice with genetic deletion of CEACAM-1, impairment of MCRI induces hyperinsulinemia and subsequently these mice develop obesity and insulin resistance (IR). Therefore, in healthy subjects, reduction of MCRI could be the primary change that induces hyperinsulinemia, obesity and IR. On the other hand, it has been shown that HCHFD induces enhanced gut permeability and endotoxemia and these changes could be a cause of IR. However, it is totally unknown whether gut microbiota and endotoxemia are related to changes in MCRI as well as insulin sensitivity after HCHFD. To address this, we recruited 21 healthy non-obese men and evaluated metabolic changes and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus 45% energy excess by supplementation with dairy fat. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and tissue specific insulin sensitivity. After the HCHFD, MCRI and muscle insulin sensitivity (M-IS) were significantly decreased by 6% and 4%, respectively. In addition, circulating lipopolysaccharide (LPS) binding protein, a marker of endotoxemia, was significantly increased by 14% after the HCHFD. Baseline relative abundance of Bacteroidetes, LPS-producing Gram-negative gut microbiota, was correlated to changes in MCRI (r=-0.57, p=0.009) and M-IS (r=-0.46, p=0.040), respectively. In conclusion, short-term HCHFD decreased MCRI and M-IS and those changes were associated with increased marker of endotoxemia after HCHFD and higher baseline relative abundance of Bacteroidetes in gut microbiota. Disclosure S. Kadowaki: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. D. Sugimoto: None. Y. Someya: None. H. Kaga: None. R. Suzuki: None. S. Kakehi: None. N. Yamasaki: None. M. Sato: None. A. Kanazawa: Speaker’s Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03196)

Serum Androgens Are Independent Predictors of Insulin Clearance but Not of Insulin Secretion in Women With PCOS.

In insulin-resistant individuals, hyperinsulinemia is a key compensatory mechanism, aimed at maintaining glucose homeostasis. Increased secretion and reduced clearance of insulin may both potentially contribute to this phenomenon. Insulin resistance and hyperinsulinemia are common findings in women with polycystic ovary syndrome (PCOS). While there is some information on insulin secretion, very few studies have investigated metabolic clearance rate of insulin (MCRI) in these women. Moreover, there is paucity of data on the relationships between MCRI and the pathophysiological characteristics of PCOS. The aim of the study was to explore these issues. One hundred ninety women with PCOS, diagnosed according to the Rotterdam criteria, with normal glucose tolerance. Assessment of MCRI and clinical, hormonal, and metabolic characteristics of subjects. MCRI and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. A historical sample of healthy women was used to define the corresponding reference intervals. MCRI was impaired in about two-thirds of women with PCOS. Subjects with low MCRI differed from those with normal MCRI for a number of anthropometric, metabolic, and endocrine features. In multivariate analysis, the degree of adiposity, estimates of insulin secretion, and serum androgen concentrations were independent predictors of MCRI. Conversely, age, adiposity, MCRI, and insulin sensitivity, but not serum androgens, were independent predictors of insulin secretion. In women with PCOS, metabolic clearance of insulin is reduced, contributing to generating hyperinsulinemia. Serum androgens are independent predictors of this phenomenon.

Diosgenin and Its Fenugreek Based Biological Matrix Affect Insulin Resistance and Anabolic Hormones in a Rat Based Insulin Resistance Model.

Fenugreek is known since ancient times as a traditional herbal medicine of its multiple beneficial effects. Fenugreek's most studied and employed effect is its hypoglycemic property, but it can also be useful for the treatment of certain thyroid disorders or for the treatment of anorexia. The regulation of glucose homeostasis is a complex mechanism, dependent on the interaction of different types of hormones and neurotransmitters or other compounds. For the study of how diosgenin and fenugreek seeds modify insulin sensitivity, we used a rat insulin resistance model induced by high-fat diet. Diosgenin in three different doses (1mg/bwkg, 10mg/bwkg, and 50 mg/bwkg, respectively) and fenugreek seed (0.2 g/bwkg) were administered orally for 6 weeks. Insulin sensitivity was determined by hyperinsulinemic euglycemic glucose clamp method. Our research group found that although glucose infusion rate was not significantly modified in either group, the increased insulin sensitivity index and high metabolic clearance rate of insulin found in the 1 mg/kg diosgenin and the fenugreek seed treated group suggested an improved peripheral insulin sensitivity. Results from the 10 mg/kg diosgenin group, however, suggest a marked insulin resistance. Fenugreek seed therapy results on the investigated anabolic hormones support the theory that, besides insulin and gastrointestinal peptides, the hypothalamic-hypopituitary axis regulated hormones synchronized action with IGF-1 also play an important role in the maintaining of normal glucose levels. Both diosgenin and fenugreek seeds are capable of interacting with substrates of the above-mentioned regulatory mechanisms, inducing serious hormonal disorders. Moreover, fenugreek seeds showed the ability to reduce the thyroid hormone levels at the periphery and to modify the T4/T3 ratio. It means that in healthy people this effect could be considered a severe side effect; however, in hypothyroidism this effect represents a possibility of alternative natural therapy.

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.

Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma. Disclosure I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.

Comprehensive assessment of insulin resistance in non-obese Asian Indian and Chinese men.

Aims/IntroductionIndian individuals are more insulin resistant (IR) than Chinese individuals, even among those with a non‐obese body mass index (BMI). However, BMI often underestimates body fat in Indian individuals, and it remains unclear whether Indians would remain more IR than Chinese individuals when both BMI and body fat are equally matched.Materials and MethodsUsing the hyperinsulinemic‐euglycemic clamp with stable‐isotope infusion, we comprehensively assessed IR between 13 non‐obese Indian men with 13 Chinese men matched for age, BMI and body fat. We further compared the differences in insulin metabolic clearance rate (MCR) between the two groups and its relationship with various metabolic parameters. The response of lipid and amino acid metabolism to insulin stimulation was also evaluated using metabolomic profiling.ResultsThe rates of endogenous glucose production during fasting were similar, and endogenous glucose production was completely suppressed during insulin clamp for both ethnic groups. Glucose disappearance during insulin clamp was also similar between the two groups, even after accounting for differences in insulin concentration. Metabolomic profiles of amino acids and various acylcarnitines were similar during both fasting and insulin clamp. However, plasma insulin during clamp was significantly higher in Indian men, indicating that insulin MCR was lower. Insulin MCR correlated significantly with total adiposity and skeletal muscle insulin sensitivity.ConclusionWhen equally matched for body fat, non‐obese Indian men had similar skeletal muscle insulin sensitivity and endogenous glucose production to Chinese men. The effects of insulin on lipid and amino acid metabolism were also similar. Low insulin MCR is associated with greater adiposity and lower skeletal muscle insulin sensitivity.

Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement.

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min-1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min-1·kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

LONG-TERM IMPROVEMENT OF GLUCOSE HOMEOSTASIS AND BODY COMPOSITION IN PATIENTS UNDERGOING LAPAROSCOPIC SLEEVE GASTRECTOMY.

Laparoscopic sleeve gastrectomy (SG) has gained popularity as a metabolic procedure, but its long-term effectiveness for Romanian patients remains unclear. To assess the long-term efficacy of SG for Romanian patients and to evaluate the differences between 5 years and 1 year follow-up. A longitudinal, prospective analysis of collected data from 68 patients undergoing SG between 2009 and 2014 was performed. Long-term outcomes at 5 years were analyzed in terms of total weight loss (%TWL), excess weight loss (%EWL), body composition and glucose homeostasis. All patients meeting the standard criteria for SG before inclusion were prospectively enrolled in the study. Of the 68 patients, eight were lost to follow-up, therefore, 60 patients (41.7±12.5 years, baseline body mass index [BMI] 44.6±9.9Kg/m2) were analyzed. The BMI decreased at 12 months with 30.7% from the preoperative BMI (p<0.001) and subsequently stabilized at 5 years.TWL and EWL were 30.6% and 83.1%, respectively at 1 year, with a slightly increase at 5 years.Therapeutic success rate (%EWL≥50) and diabetes remission rate (Buchwald criteria) were 93.3% and respectively 63.6% at 5 years. Insulin sensitivity index and metabolic clearance rate of glucose increased with 92.5% and 60.1% respectively, in the third month from baseline (p<0.001), while estimated second phase of insulin secretion decreased with 7.9% in the first month postoperatively (p=0.04), remaining stable afterwards. SG was effective in terms of %EWL, body composition and glucose homeostasis improvement for Romanian patients, the outcomes stabilizing after 1 year follow-up.

Maternal methyl donor and cofactor supplementation in late pregnancy increases β-cell numbers at 16 days of life in growth-restricted twin lambs.

Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at days 12-14 in singleton controls (CON, n = 7 lambs from 7 ewes), twins (IUGR, n = 8 lambs from 8 ewes), and twins from ewes that received MMDS (2 g rumen-protected methionine, 300 mg folic acid, 1.2 g sulfur, 0.7 mg cobalt) daily from 120 days after mating (~0.8 of term) until delivery (IUGR+MMDS, n = 8 lambs from 4 ewes). Body composition and pancreas morphometry were assessed in lambs at day 16 IUGR reduced size at birth and increased neonatal fractional growth rate. MMDS normalized long bone lengths but not other body dimensions of IUGR lambs at birth. IUGR did not impair glucose control or insulin action at days 12-14, compared with controls. MMDS increased metabolic clearance rate of insulin and increased β-cell numerical density and tended to improve insulin sensitivity, compared with untreated IUGR lambs. This demonstrates that effects of late-pregnancy methyl donor supplementation persist until at least the third week of life. Whether these effects of MMDS persist beyond early postnatal life and improve metabolic outcomes after IUGR in adults and the underlying mechanisms remain to be determined.

Correlates of insulin clearance in apparently healthy non-obese Japanese men

Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappearance (Rd) during the clamp and muscle insulin sensitivity was defined as Rd/steady state serum insulin (SSSI) at the second step. Based on the median value of MCRI, the subjects were divided into the low- and high-MCRI groups. Subjects of the low-MCRI group had significant impairment of muscle insulin sensitivity, although Rd levels were comparable between the two groups, probably due to elevated SSSI in the low-MCRI group. Subjects of the low-MCRI group had higher total body fat content and lower VO2peak and showed no deterioration of cardiometabolic risk factors. Our results suggest that low MCRI may be early change to maintain glucose uptake and metabolic status in the face of slight impairment of muscle insulin sensitivity caused by increased adiposity and lower fitness level.