scholarly journals New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

2021 ◽  
Author(s):  
Roberto Bizzotto ◽  
Domenico Tricò ◽  
Andrea Natali ◽  
Amalia Gastaldelli ◽  
Elza Muscelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Β Cell ◽  
Euglycemic Clamp ◽  
Glucose Ingestion ◽  
Per Se

<i>Objective</i> Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. <p><i>Research Design and Methods</i> We estimated standardized EIC (EIC<sub>ISR</sub>) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EIC<sub>ISR</sub> association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).</p> <p><i>Results</i> Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC<sub>ISR</sub>, ~4 times more influential than insulin-resistance related hypersecretion. EIC<sub>ISR</sub> independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.</p> <p><i>Conclusions</i> Based on EIC<sub>ISR</sub>, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC<sub>ISR</sub> with insulin resistance (not with higher BMI <i>per se</i>) and is more relevant than the concomitant hypersecretion; the second reduces EIC<sub>ISR</sub> with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br> </p>

scholarly journals New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

2021 ◽  
Author(s):  
Roberto Bizzotto ◽  
Domenico Tricò ◽  
Andrea Natali ◽  
Amalia Gastaldelli ◽  
Elza Muscelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Β Cell ◽  
Euglycemic Clamp ◽  
Glucose Ingestion ◽  
Per Se

<i>Objective</i> Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. <p><i>Research Design and Methods</i> We estimated standardized EIC (EIC<sub>ISR</sub>) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EIC<sub>ISR</sub> association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).</p> <p><i>Results</i> Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC<sub>ISR</sub>, ~4 times more influential than insulin-resistance related hypersecretion. EIC<sub>ISR</sub> independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.</p> <p><i>Conclusions</i> Based on EIC<sub>ISR</sub>, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC<sub>ISR</sub> with insulin resistance (not with higher BMI <i>per se</i>) and is more relevant than the concomitant hypersecretion; the second reduces EIC<sub>ISR</sub> with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br> </p>

scholarly journals High-Fat Diet Accelerates Pathological Progression and Intestinal Inflammation in a Type 2 Diabetes Rodent Model

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A446-A446
Author(s):  
Austin Reilly ◽  
Hongxia Ren
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Pathway Analysis ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Intestinal Inflammation ◽  
Oral Glucose ◽  
Gi Tract ◽  
High Fat

Abstract Insulin signaling lowers postprandial glucose by stimulating cell surface translocation of the insulin sensitive glucose transporter 4 (GLUT4). In order to better understand how insulin resistance contributes to the pathophysiological progression of type 2 diabetes, we generated human GLUT4 promoter-driven insulin receptor knockout (GIRKO) mice and characterized their metabolic features relative to control mice. Although the role of insulin resistance in diabetes is beyond dispute, our previous studies showed that GIRKO mice fed normal chow diet (NCD) had an unexpectedly low rate of frank diabetes despite severe insulin resistance in muscle, fat, and brain. In the current study, we first sought to determine whether GIRKO mice would respond to high-fat diet (HFD) challenge with worsened glycemic outcome compared to control mice on HFD. Secondly, we sought to determine whether HFD-induced pathologies in GIRKO mice were caused by adaptations in the gastrointestinal (GI) tract and microbiome. We discovered that after beginning the HFD-feeding regimen, GIRKO mice rapidly developed hyperinsulinemia and hyperglycemia without excessive adiposity gain. Furthermore, GIRKO mice displayed dyslipidemia via increased hepatic lipid accumulation and serum lipid content. We used indirect calorimetry to characterize the metabolic features of single-housed mice. HFD-fed GIRKO mice had comparatively lower respiratory exchange ratio (RER), indicating relatively greater lipid metabolism compared to control mice on HFD. Despite having increased circulating incretins, GIRKO mice had impaired oral glucose tolerance and limited glucose-lowering benefit from Exendin-4 (Ex-4) injections. Since HFD promotes inflammation in the gastrointestinal (GI) tract, we performed gene expression analysis and pathway analysis of duodenal mRNAs to investigate whether inflammatory response, glucose transport, and lipid transport were altered in HFD-fed GIRKO mice. Among the top pathways discovered in pathway analysis were those involved with inflammatory signaling, carbohydrate transport, and xenobiotic metabolism, which supports that HFD-fed GIRKO mice have increased GI tract inflammation which may promote impaired glucose homeostasis. In conclusion, our studies suggest that HFD increased intestinal inflammation and exacerbated insulin resistance, which catalyzed the pathological progression of diabetes. Future studies are necessary to identify the molecular and cellular signaling pathways which culminate in frank diabetes, which may lead to therapeutic targets for regulating glucose homeostasis in the context of insulin resistance.

scholarly journals Metabolic Footprint, towards Understanding Type 2 Diabetes beyond Glycemia

2020 ◽  
Vol 9 (8) ◽  
pp. 2588 ◽  
Author(s):  
Ana F. Pina ◽  
Rita S. Patarrão ◽  
Rogério T. Ribeiro ◽  
Carlos Penha-Gonçalves ◽  
João F. Raposo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cluster Analysis ◽  
Tolerance Test ◽  
Insulin Clearance ◽  
Oral Glucose ◽  
Alcoholic Fatty Liver ◽  
Specific Insulin ◽  
Alcoholic Fatty Liver Disease

Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects (PREVADIAB2 cohort) with normoglycemia, prediabetes, or non-treated diabetes. The algorithm was informed by age, anthropometry, and metabolic milieu (glucose, insulin, C-peptide, and free fatty acid (FFA) levels during the oral glucose tolerance test OGTT). For cluster profiling, we additionally used indexes of metabolism mechanisms (e.g., tissue-specific insulin resistance, insulin clearance, and insulin secretion), non-alcoholic fatty liver disease (NAFLD), and glomerular filtration rate (GFR). We found prominent heterogeneity within two optimal clusters, mainly representing normometabolism (Cluster-I) or insulin resistance and NAFLD (Cluster-II), at higher granularity. This was illustrated by sub-clusters showing similar NAFLD prevalence but differentiated by glycemia, FFA, and GFR (Cluster-II). Sub-clusters with similar glycemia and FFA showed dissimilar insulin clearance and secretion (Cluster-I). This work reveals that T2D heterogeneity can be captured by a thorough metabolic milieu and mechanisms profiling—metabolic footprint. It is expected that deeper phenotyping and increased pathophysiology knowledge will allow to identify subject’s multidimensional profile, predict their progression, and treat them towards precision medicine.

Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

2005 ◽  
Vol 288 (4) ◽  
pp. E707-E714 ◽  
Author(s):  
Marcela Brissova ◽  
Michael Blaha ◽  
Cathi Spear ◽  
Wendell Nicholson ◽  
Aramandla Radhika ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Glucose Disposal ◽  
Β Cell ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1+/−, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/−, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/−;PDX-1+/−). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/−;PDX-1+/− mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.

scholarly journals Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors

2021 ◽  
Vol 18 (2) ◽  
pp. 716
Author(s):  
Francesca Farrugia ◽  
Alexia Aquilina ◽  
Josanne Vassallo ◽  
Nikolai Paul Pace
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bisphenol A ◽  
Glucose Homeostasis ◽  
Metabolic Effects ◽  
Pancreatic Β Cell ◽  
Β Cell

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and eventual pancreatic β-cell dysfunction, resulting in persistent high blood glucose levels. Endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) are currently under scrutiny as they are implicated in the development of metabolic diseases, including T2DM. BPA is a pervasive EDC, being the main constituent of polycarbonate plastics. It can enter the human body by ingestion, through the skin, and cross from mother to offspring via the placenta or breast milk. BPA is a xenoestrogen that alters various aspects of beta cell metabolism via the modulation of oestrogen receptor signalling. In vivo and in vitro models reveal that varying concentrations of BPA disrupt glucose homeostasis and pancreatic β-cell function by altering gene expression and mitochondrial morphology. BPA also plays a role in the development of insulin resistance and has been linked to long-term adverse metabolic effects following foetal and perinatal exposure. Several epidemiological studies reveal a significant association between BPA and the development of insulin resistance and impaired glucose homeostasis, although conflicting findings driven by multiple confounding factors have been reported. In this review, the main findings of epidemiological and functional studies are summarised and compared, and their respective strengths and limitations are discussed. Further research is essential for understanding the exact mechanism of BPA action in various tissues and the extent of its effects on humans at environmentally relevant doses.

scholarly journals Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

2021 ◽  
pp. 100013
Author(s):  
Froylan David Martínez-Sánchez ◽  
Valerie Paola Vargas-Abonce ◽  
Andrea Rocha-Haro ◽  
Romina Flores-Cardenas ◽  
Milagros Fernández-Barrio ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
At Risk ◽  
Insulin Secretion ◽  
Visceral Adiposity ◽  
Visceral Adiposity Index ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

scholarly journals Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 7797
Author(s):  
Joseph A. M. J. L. Janssen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Insulin Secretion ◽  
Early Stage ◽  
Insulin Clearance ◽  
Future Research ◽  
Age Related ◽  
Hepatic Insulin Clearance

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

scholarly journals Development of a Nongenetic Mouse Model of Type 2 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Elizabeth R. Gilbert ◽  
Zhuo Fu ◽  
Dongmin Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Serum Insulin ◽  
Cell Mass ◽  
Low Fat ◽  
Β Cell ◽  
Islet Mass ◽  
Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

The role of vitamin D in the development of type 2 diabetes

2021 ◽  
Vol 19 (1) ◽  
pp. 44-52
Author(s):  
A.P. Shumilov ◽  
◽  
M.Yu. Semchenkova ◽  
D.S. Mikhalik ◽  
T.G. Avdeeva ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Inverse Relationship ◽  
Biological Mechanisms ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Vitamin D Levels

Vitamin D plays an important role in decreasing the risk of developing type 2 diabetes by influencing calcium metabolism, thereby reducing β-cell dysfunction and preventing insulin resistance. The findings of research works are contradictory enough, although some of them demonstrated an inverse relationship between vitamin D levels and the incidence of type 2 diabetes. The article describes the biological mechanisms of relationships between vitamin D levels and type 2 diabetes, reviews the results of the studies conducted and summarizes the available data. Key words: vitamin D, type 2 diabetes mellitus, insulin resistance

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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