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  • 1
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    Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 3 ( 2023-03-01), p. 362-366
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 3 ( 2023-03-01), p. 362-366
    Abstract: The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide–based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P & lt; 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction & lt; 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0441
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 2
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    Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 2 ( 2020-02-01), p. 298-305
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 2 ( 2020-02-01), p. 298-305
    Abstract: To evaluate whether the sodium–glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of −1.8% (95% CI −3.4, −0.2; P = 0.02) and relative change in LFC of −22% (−36, −7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change −2.5 kg [−3.7, −1.4]; P & lt; 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (−74 mol/L [−108, −42]; P & lt; 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P & lt; 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-0641
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 3
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    Fatty Liver Is Independently Associated With Alterations in Circulating HDL2 and HDL3 Subfractions
    American Diabetes Association ; 2008
    In:  Diabetes Care Vol. 31, No. 2 ( 2008-02-01), p. 366-368
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 31, No. 2 ( 2008-02-01), p. 366-368
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc07-1558
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2008
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  • 4
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    Association of Type 2 Diabetes Candidate Polymorphisms in KCNQ1 With Incretin and Insulin Secretion
    American Diabetes Association ; 2009
    In:  Diabetes Vol. 58, No. 7 ( 2009-07-01), p. 1715-1720
    Details
    In: Diabetes, American Diabetes Association, Vol. 58, No. 7 ( 2009-07-01), p. 1715-1720
    Abstract: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered β-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli. RESEARCH DESIGN AND METHODS We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli. RESULTS rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P ≤ 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P & lt; 0.05). No SNPs were associated with β-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P ≥ 0.05). CONCLUSIONS Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db08-1589
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2009
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  • 5
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    148-OR: Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans with Prediabetes
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates adiposity. In most cases of obesity and diabetes, the brain becomes insulin resistant with impaired brain-derived modulation of peripheral metabolism. As treatment with the SGLT2-inhibitor empagliflozin not only improves glucose metabolism but also reduces body weight and cardiovascular risk, we hypothesized that improved brain insulin sensitivity could be involved. Methods: In this double blind study, 40 participants with prediabetes (according to ADA’s OGTT criteria) were 1:1 randomized to receive 25 mg empagliflozin qd or placebo (mean ± SD: age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²). Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with the intranasal administration of insulin to the brain. Results: In healthy persons, intranasal insulin administration significantly decreases cerebral blood flow in the hypothalamus. In the current study, volunteers with prediabetes were unresponsive to this, as insulin could not induce hypothalamic inhibition prior treatment. We identified a significant interaction between treatment and the hypothalamic response to insulin (p & lt;0.05, corrected for multiple comparisons). Post-hoc analyses showed that only participants on empagliflozin showed a significant insulin-induced decrease in hypothalamic blood flow after treatment. The group receiving placebo showed no such improvement. Conclusion: Our current results corroborate insulin resistance of the human hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the positive effects of SGLT2 inhibitors. These findings reveal that brain insulin resistance is treatable by pharmacological interventions with potential benefits for cognition, adiposity, and whole-body metabolism. Disclosure M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S. Kullmann: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. J. Hummel: None. C. Dannecker: None. A. Vosseler: None. L. Fritsche: None. K. Kantartzis: None. J. Machann: None. H. Haering: None. A. Fritsche: None. H. Preissl: None. Funding Boehringer Ingelheim
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-148-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 6
    Online Resource
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    Circulating Palmitoleate Strongly and Independently Predicts Insulin Sensitivity in Humans
    American Diabetes Association ; 2010
    In:  Diabetes Care Vol. 33, No. 2 ( 2010-02-01), p. 405-407
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 33, No. 2 ( 2010-02-01), p. 405-407
    Abstract: We investigated whether palmitoleate, which prevents insulin resistance in mice, predicts insulin sensitivity in humans. RESEARCH DESIGN AND METHODS The fasting fatty acid pattern in the plasma free fatty acid (FFA) fraction was determined in 100 subjects at increased risk for type 2 diabetes. Insulin sensitivity was estimated during an oral glucose tolerance test (OGTT) at baseline and after 9 months of lifestyle intervention and measured during the euglycemic-hyperinsulinemic clamp (n = 79). RESULTS Circulating palmitoleate (OGTT:F ratio = 8.2, P = 0.005; clamp:F ratio = 7.8, P = 0.007) but not total FFAs (OGTT:F ratio = 0.6, P = 0.42; clamp:F ratio = 0.7, P = 0.40) correlated positively with insulin sensitivity, independently of age, sex, and adiposity. High baseline palmitoleate predicted a larger increase in insulin sensitivity. For 1-SD increase in palmitoleate, the odds ratio for being in the highest versus the lowest tertile of adjusted change in insulin sensitivity was 2.35 (95% CI 1.16–5.35). CONCLUSIONS Circulating palmitoleate strongly and independently predicts insulin sensitivity, suggesting that it plays an important role in the pathophysiology of insulin resistance in humans.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc09-0544
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
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  • 7
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    133-OR: Effects of Empagliflozin on Liver Fat Content in Type 2 Diabetes: The EMLIFA001 Trial
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Type 2 diabetes (T2D) associates with nonalcoholic fatty liver disease (NAFLD), which itself contributes to both insulin resistance and excessive cardiovascular risk of diabetes. Nevertheless, there is currently no established therapy for NAFLD in T2D. This trial examined whether treatment with the sodium glucose transporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (HCL, primary outcome) in metabolically well-controlled patients with short known disease duration. T2D patients (n=84; 63±8 years; body mass index (BMI) 32.2±4.5 kg/m2, HbA1c 6.6±0.5%, disease duration 38±27 months) were randomly assigned to 24-week treatment with either EMPA 25 mg per day or placebo (PLAC). HCL was measured by 1H-magnetic resonance (MR) spectroscopy (STEAM) and fat-selective MR imaging (IDEAL). Statistical analysis was done by ANCOVA adjusted for the respective baseline value, age, sex and BMI. After treatment, HCL was reduced compared to baseline (relative change (RC) EMPA -33%[95% confidence interval -43;-23], p & lt;0.0001; PLAC -14[-23;-3]%, p=0.014) and different between the two interventions (p=0.007). Body weight (BW) decreased with EMPA but not with PLAC (least square means (LSM): -2.7±0.4 kg, p & lt;0.0001, vs. 0 .06±0.5 kg). Causal mediation analysis revealed that reduction of HCL was mainly driven by weight loss. Serum adiponectin levels rose markedly with EMPA only (LSM EMPA 458±102, p & lt;0.0001; PLAC -63±105 ng/ml; EMPA vs. PLAC p=0.0008), whereas tumor necrosis factor α (TNFα) was unchanged in both groups (RC TNFα 0.1[-11.3;13.0] vs. -0.1[-8.1;8.6] %). Δadiponectin neither correlated with ΔHCL nor with ΔBW, but inversely correlated with changes in serum cytokeratin-18 (CK18) M30 fragment in the EMPA group only (β=-3.0, p=0.014). In conclusion, empagliflozin effectively reduces HCL in well-controlled T2D patients and increases serum adiponectin with beneficial effects on hepatocellular integrity. Thus, empagliflozin may improve NAFLD via distinct different mechanisms. Disclosure S. Kahl: None. S. Gancheva: None. K. Strassburger: None. C. Herder: None. J. Machann: None. H. Katsuyama: None. S. Kabisch: Research Support; Self; California Walnut Commission, Institute for Grain Processing, Nuthetal, J. Rettenmaier Söhne, Südzucker / Beneo. Other Relationship; Self; Berlin-Chemie AG, Sanofi. E. Henkel: None. S. Kopf: None. K. Kantartzis: None. Y. Kupriyanova: None. O. Kuss: None. J. Hwang: None. C. Kasperk: None. N. Stefan: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi. A.F. Pfeiffer: Advisory Panel; Self; Abbott, Berlin-Chemie AG, Novo Nordisk A/S. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG, Sanofi-Aventis Deutschland GmbH. A.L. Birkenfeld: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding Boehringer Ingelheim Pharma GmbH
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-133-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 8
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    The −8503 G/A Polymorphism of the Adiponectin Receptor 1 Gene Is Associated With Insulin Sensitivity Dependent on Adiposity
    American Diabetes Association ; 2006
    In:  Diabetes Care Vol. 29, No. 2 ( 2006-02-01), p. 464-464
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 29, No. 2 ( 2006-02-01), p. 464-464
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.29.02.06.dc05-2020
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
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  • 9
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    Relationships of Circulating Sex Hormone–Binding Globulin With Metabolic Traits in Humans
    American Diabetes Association ; 2010
    In:  Diabetes Vol. 59, No. 12 ( 2010-12-01), p. 3167-3173
    Details
    In: Diabetes, American Diabetes Association, Vol. 59, No. 12 ( 2010-12-01), p. 3167-3173
    Abstract: Recent data suggested that sex hormone–binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes. RESEARCH DESIGN AND METHODS Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by 1H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (ISOGTT) and measured by a euglycemic hyperinsulinemic clamp (ISclamp, n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172). RESULTS SHBG levels correlated positively with insulin sensitivity (ISOGTT, P = 0.037; ISclamp, P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (ISOGTT, P = 0.0096; ISclamp, P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = −0.17, P = 0.009) and after (r = −0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P ≤ 0.025) but not with metabolic characteristics (all P & gt; 0.18). CONCLUSIONS Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db10-0179
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
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  • 10
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    1099-P: Effects of Empagliflozin on Glucose Metabolism and Body Fat Composition in Patients with Prediabetes: A Randomized, Double-Blind, Placebo-Controlled Trial
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Objective: In patients with diabetes, the beneficial effects of empagliflozin on glucose metabolism, body adiposity, and liver fat content are well established. As the mode of action of SGLT2 inhibitors partly depends on elevated blood glucose, we investigated if these effects also occur in prediabetes. Methods: Forty participants with prediabetes (mean ± SD: age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²; FG: 5.98 ± 0.57 mmol/l) were randomized to receive 25 mg empagliflozin qd or placebo for 8 weeks. Before and after treatment, all participants underwent a 75 g oral glucose tolerance test to evaluate glucose tolerance, peripheral insulin sensitivity and insulin secretion. Body fat was assessed by whole-body MRI and intrahepatic fat by localized MR-spectroscopy. Resting energy expenditure and respiratory quotient (RQ) were assessed by indirect calorimetry at fast. “Per protocol” analysis using ANCOVA was performed. Results: Fasting glucose, glucose tolerance, peripheral insulin sensitivity, and insulin secretion were not significantly changed by treatment. Though, after 8 weeks of treatment, total adipose tissue (mean difference between groups at the end of study ± SEM: 3.1 ± 2.3 liters; p=0.034) and intrahepatic fat (2.1 ± 2.3 %; p=0.029) were lower in patients who received empagliflozin, compared to placebo. Empagliflozin treatment resulted in a lower RQ compared to placebo (p=0.022) without differences in resting energy expenditure (p=0.2), indicating preferential lipid oxidation upon treatment. Conclusion: In prediabetes, treatment with empagliflozin for 8 weeks has no major effects on glucose metabolism. However, this SGLT2 inhibitor reduced body adiposity and liver fat content, presumably by shifting energy metabolism towards lipid oxidation. Therefore, empagliflozin might represent a treatment option for obesity and hepatic steatosis in prediabetes, independent of drug effects on blood glucose. Disclosure J. Hummel: None. C. Dannecker: None. L. Fritsche: None. A. Vosseler: None. K. Kantartzis: None. S. Kullmann: None. J. Machann: None. H. Preissl: None. H. Haering: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. Funding Boehringer Ingelheim
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1099-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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