Insulin sensitivity predicts cognitive decline in individuals with prediabetes

IntroductionEpidemiological studies indicate an association between type 2 diabetes and cognitive dysfunction that appear to start already in the prediabetic state. Although cross-sectional studies have linked insulin resistance to impaired cognition, the potential predictive value of insulin resistance has not yet been sufficiently studied longitudinally without confounding by overt diabetes (and its pharmacological treatment).Research design and methodsWe investigated longitudinal data from participants of the ‘Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration’ Study. Subjects underwent a neurocognitive assessment battery (CERAD Plus battery; Consortium to Establish a Registry for Alzheimer’s Disease) at baseline and followed every 2 years (median follow-up 4.0 Q1–3: 2.2–4.3 years). Subjects within a pre-diabetic glycated hemoglobin range of 5.6%–6.5% underwent 5-point 75 g oral glucose tolerance tests (OGTTs) with assessment of insulin sensitivity and insulin secretion (n=175). Subjects with newly diagnosed diabetes mellitus or with major depressivity (Beck Depression Inventory >20) were excluded (n=15). Data were analyzed by mixed models using sex, age and glycemic trait as fixed effects. Subject and time since first measurement were used as random effects.ResultsInsulin sensitivity was positively associated with the CERAD sum score (higher is better) in a time-dependent manner (p=0.0057). This result is mainly driven by a steeper decrease in the memory domain associated with lower insulin sensitivity (p=0.029). The interaction between age and insulin sensitivity was independent of glycemia (p=0.02). There was also no association between insulin secretion and cognition.ConclusionsInsulin resistance rather than sole elevation of blood glucose predicts cognitive decline, specifically in the memory domain, in persons with prediabetes. Treatments of diabetes that improve insulin sensitivity might therefore have the potential to postpone or even prevent cognitive decline in patients with diabetes.

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Microbiota-related metabolites and the risk of type 2 diabetes

10.2337/dc20-1234/suppl.12009102 ◽

2020 ◽

Author(s):

Jagadish Vangipurapu ◽

Lilian Fernandes Silva ◽

Teemu Kuulasmaa ◽

Ulf Smith ◽

Markku Laakso

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Microbial Metabolites ◽

Cross Sectional ◽

Metabolomics Data ◽

Incident Type ◽

Increased Risk

OBJECTIVE: Recent studies have highlighted the significance of microbiome in human health and disease. Changes in the metabolites produced by microbiota have been implicated in several diseases. Our objective was to identify microbiome metabolites that are associated with type 2 diabetes. RESEARCH DESIGN AND METHODS: 5,181 participants from the cross-sectional METabolic Syndrome In Men (METSIM) study that included Finnish men (age 57 ± 7 years, body mass index 26.5 ± 3.5 kg/m2) having metabolomics data available were included in our study. Metabolomics analysis was performed based on fasting plasma samples. Based on an oral glucose tolerance test, Matsuda ISI and Disposition index were calculated as markers of insulin sensitivity and insulin secretion. A total of 4,851 participants had a 7.4-year follow-up visit and 522 participants developed type 2 diabetes. RESULTS: Creatine, 1-palmitoleoylglycerol(16:1), urate, 2-hydroxybutyrate/2-hydroxyisobutyrate, xanthine, xanthurenate, kynurenate, 3-(4-hydroxyphenyl)lactate, 1-oleoylglycerol(18:1), 1-myristoylglycerol(14:0), dimethylglycine and 2-hydroxyhippurate(salicylurate) were significantly associated with an increased risk of type 2 diabetes. These metabolites were associated with decreased insulin secretion or insulin sensitivity or both. Among the metabolites that were associated with a decreased risk of type 2 diabetes, 1-linoleoyl-glycerophosphocholine (18:2) significantly reduced the risk of type 2 diabetes. CONCLUSIONS: Several novel and previously reported microbial metabolites related to gut microbiota were associated with an increased risk of incident type 2 diabetes, and they were also associated with decreased insulin secretion and insulin sensitivity. Microbial metabolites are important biomarkers for the risk of type 2 diabetes.

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Microbiota-related metabolites and the risk of type 2 diabetes

10.2337/dc20-1234/suppl.12009102.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jagadish Vangipurapu ◽

Lilian Fernandes Silva ◽

Teemu Kuulasmaa ◽

Ulf Smith ◽

Markku Laakso

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Microbial Metabolites ◽

Cross Sectional ◽

Metabolomics Data ◽

Incident Type ◽

Increased Risk

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Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01808 ◽

2018 ◽

Vol 104 (5) ◽

pp. 1855-1865 ◽

Cited By ~ 14

Author(s):

Kristina M Utzschneider ◽

Steven E Kahn ◽

David C Polidori

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Body Fat ◽

Subcutaneous Fat ◽

Insulin Clearance ◽

Liver Fat ◽

Glucose Disposal ◽

Oral Glucose ◽

Cross Sectional ◽

Hepatic Insulin Extraction

Abstract Context Total insulin clearance is decreased in nonalcoholic fatty liver disease (NAFLD), but the relationship between liver fat and hepatic insulin extraction (HIE) is unknown. Objective This cross-sectional study addresses the hypothesis that HIE is reduced in NAFLD and investigates metabolic and/or anthropometric characteristics most closely associated with insulin clearance. Participants Nondiabetic subjects with NAFLD (n = 13) and age- and body mass index (BMI)-matched controls with normal liver enzymes (n = 15) underwent abdominal CT, dual-energy X-ray absorptiometry, oral glucose tolerance test (OGTT), and labeled two-step hyperinsulinemic-euglycemic clamps. Outcome Measurements Liver fat was estimated by the CT liver/spleen ratio. Hepatic and extrahepatic insulin clearances were modeled using clamp and OGTT data. Results Extrahepatic insulin clearance and HIE were not different between NAFLD and controls and did not correlate with liver fat. HIE was positively correlated with insulin sensitivity [rate of glucose disposal (Rd; low r = +0.7, P < 0.001; high r = +0.6, P = 0.001), adiponectin (r = +0.55, P = 0.004), and insulin-mediated suppression of clamp nonesterified free fatty acid (NEFA; r = +0.67, P < 0.001)] but was not associated with fasting NEFA, insulin-mediated suppression of glucose production, or measures of adiposity. Extrahepatic insulin clearance was positively associated with percent body fat (r = +0.44, P = 0.02) and subcutaneous fat (r = +0.42, P = 0.03) but not BMI, intra-abdominal fat, liver fat, Rd, adiponectin, or NEFA. Conclusions HIE is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin resistance. The data suggest differential regulation of insulin clearance with extrahepatic insulin clearance being associated with body fat and not insulin sensitivity.

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Insulin Sensitivity Measured with the Oral Minimal Model is lower in Obese Subjects Who Report omitting their Breakfast

Integrative Diabetes and Cardiovascular Diseases ◽

10.18314/idcd.v3i1.1873 ◽

2019 ◽

pp. 134-145

Author(s):

Brun JF ◽

Delbos C ◽

Gimet F ◽

Raynaud de Mauverger E ◽

Mercier J

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Minimal Model ◽

Cross Sectional Study ◽

Oral Glucose ◽

Sectional Study ◽

Cross Sectional ◽

Obese Subjects ◽

Oral Minimal Model

Introduction: Omitting the breakfast has been reported to promote weight gain and to impair insulin sensitivity. However this latter effect was only assessed with simple surrogates. We thus aimed at verifying if insulin sensitivity is lowered in individuals who omit their breakfast with a more quantitative assessment, using the “Oral Minimal Model” (OMM) i.e., an extension of Bergman’s minimal model to oral glucose tolerance-tests, in a cross-sectional study of a population exhibiting the full range of body mass indices.Materials and methods: We selected on our database of patients, explored for weight and/or eating disorders, 27 individuals omitting their breakfast (defined on the basis of an alimentary standardized questionnaire) and compared them to 103 matched subjects taking a hyperglucidic breakfast. The breakfast was analyzed with the OMM for the assessment of insulin sensitivity. Insulin secretion was assessed with a previously reported procedure, allowing the calculation of the parameters of phase 1 and 2 of insulin secretion of Cobelli and Mari’s models. In addition, it is already known that Mari’s model provides an index of post stimulatory potentiation of insulin secretion. Disposition indices (product of SI and insulin secretion parameters) were also determined.Results: In the 27 subjects omitting their breakfast compared to the 103 matched subjects the difference in insulin sensitivity was not found. No difference in insulin secretion parameters is detected. Homeostasis between insulin secretion and insulin sensitivity appears to be functional. However when splitting the sample in categories of BMI the expected difference appears in the range 30-40. In this subgroup (Omitting (n=9) BMI: 35.4±0.99 vs. non-omitting (n=47) BMI: 34.1±0.37 kg/m²) insulin sensitivity was lower in individuals omitting their breakfast (4.32 10-4 min-1/(μU/ml)± 0.94 vs. 9.33±1.84, p=0.03). Despite a slight increase in insulin levels and in the overall insulin secretion rate, a decrease in potentiation and in disposition index was evidenced in individuals omitting their breakfast. The lowering effect of omitting the breakfast on insulin sensitivity is thus evidenced in obese subjects in this sample (but not in those with a BMI below 30). This impairment in insulin sensitivity resulted in a decrease of glucose tolerance by 34%. This finding, based on a cross-sectional study but using a sophisticated measurement, is in agreement with the previous report that omission of the breakfast may induce resistance to insulin. It suggests that the worsening effect on SI that was experimentally found in an interventional study in healthy women becomes important enough in obese subjects to be detected in a cross-sectional study, and that this effect associates a decrease in SI and an incomplete adaptation of insulin release to this reduction in SI, and thus a decrease in glucose tolerance.

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Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort

Experimental Biology and Medicine ◽

10.1177/15353702211009493 ◽

2021 ◽

pp. 153537022110094

Author(s):

Ibiye Owei ◽

Nkiru Umekwe ◽

Frankie Stentz ◽

Jim Wan ◽

Sam Dagogo-Jack

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Intravenous Glucose Tolerance Test ◽

Cross Sectional ◽

Parental History ◽

Intravenous Glucose

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

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The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

Clinical Chemistry ◽

10.1373/clinchem.2010.153726 ◽

2011 ◽

Vol 57 (2) ◽

pp. 309-316 ◽

Cited By ~ 73

Author(s):

Greisa Vila ◽

Michaela Riedl ◽

Christian Anderwald ◽

Michael Resl ◽

Ammon Handisurya ◽

...

Keyword(s):

Insulin Resistance ◽

Gastric Bypass ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Model Assessment ◽

Obese Patients ◽

Growth Differentiation Factor 15 ◽

Homeostatic Model Assessment ◽

Homeostatic Model ◽

The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

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A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00573.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1358-E1363 ◽

Cited By ~ 47

Author(s):

Arvinder K. Dhalla ◽

Mei Yee Wong ◽

Peter J. Voshol ◽

Luiz Belardinelli ◽

Gerald M. Reaven

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Adenosine Receptor ◽

Infusion Rate ◽

Glucose Infusion ◽

Glucose Infusion Rate ◽

Oral Glucose ◽

Acute Administration ◽

High Fat ◽

Adenosine Receptor Agonist

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A1 adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly ( P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

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Chronic kidney disease and obesity bias surrogate estimates of insulin sensitivity compared with the hyperinsulinemic euglycemic clamp

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00394.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. E175-E182 ◽

Cited By ~ 2

Author(s):

Iram Ahmad ◽

Leila R. Zelnick ◽

Nicole R. Robinson ◽

Adriana M. Hung ◽

Bryan Kestenbaum ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Insulin Sensitivity ◽

Kidney Disease ◽

Oral Glucose ◽

Cross Sectional ◽

Euglycemic Clamp ◽

Insulin Kinetics ◽

Hyperinsulinemic Euglycemic Clamp ◽

Sensitivity Indices ◽

Organ Specific

Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross-sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) <60 ml·min−1·1.73 m2] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8–38% lower in participants with vs. without CKD and 13–59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD ( P = 0.09) and 36% lower in participants with vs. without obesity ( P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD ( P = 0.02) and 46% lower in participants with vs. without obesity ( P < 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin.

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Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00606.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. E920-E929 ◽

Cited By ~ 23

Author(s):

Esben S. Buhl ◽

Thomas Korgaard Jensen ◽

Niels Jessen ◽

Betina Elfving ◽

Christian S. Buhl ◽

...

Keyword(s):

Insulin Resistance ◽

Birth Weight ◽

Insulin Sensitivity ◽

Low Birth Weight ◽

Mrna Expression ◽

Hpa Axis ◽

Whole Body ◽

Oral Glucose ◽

Red Muscle ◽

Hpa Axis Activity

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4–5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phospho enolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser473phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW ( P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion ( P < 0.05 vs. Cx), whole body insulin resistance ( P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression ( P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser473phosphorylation. The ESC treatment normalized corticosterone secretion ( P < 0.05 vs. LBW), whole body insulin sensitivity ( P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression ( P < 0.05), and red muscle PKB Ser473phosphorylation ( P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

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