The Journal of Clinical Endocrinology and Metabolism, Apr 9, 2022
Context Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia an... more Context Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. Objective To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. Methods PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. Results The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was −27.3% (CI –36.5% to –18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. Conclusion The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.
The metabolic and hemodynamic correlates of SGLT2i-mediated UGE in patients with diabetes are not... more The metabolic and hemodynamic correlates of SGLT2i-mediated UGE in patients with diabetes are not well understood. Accordingly, in this post hoc analysis, we measured UGE in 66 T2D, 37 T1D, and 25 nondiabetic (ND) participants under baseline conditions and following treatment with an SGLT2i (empagliflozin, 25 mg/d, EMPA). Measurements were taken during 3 h of fasting and 5 h of a mixed meal absorption (T2D and ND) or under usual clinical conditions in patients with T1D. Fractional glucose excretion (FEGlu) was obtained as the ratio of UGE to the filtered glucose load (=GFR x plasma glucose concentration [G]). In T1D participants only, ERPFPAH and GFRINULIN were measured and intraglomerular pressure (PGLO) estimated. With EMPA, FEGlu was 38±12% and 46±11% in T2D (fasting and post meal, respectively), 26±11% and 36±8% in ND, and 45±21% in T1D. In the pooled T1D, T2D and ND cohort, overall effect of EMPA on FEGlu was 39±11%; in this model, [G] was a positive determinant (FEGlu=34% at a [G] of 100 mg/dL and 44% at a [G] of 200 mg/dL, r=0.38, p<0.0001), whereas presence of T1D, T2D or ND was not. After adjusting for [G], plasma insulin concentration was also a positive determinant of FeGlu (r=0.12, p=0.01), adding 3% to FEGlu at the mean post meal plasma insulin of 50 µU/mL in T2D and ND; likewise, in T1D, FEGlu was related to the mean daily insulin dose (r=0.41, p<0.01). As described in previous work, in T1D, EMPA decreased ERPF and increased renal vascular resistance (p<0.01). Estimated PGLO was reduced (59.0±6.7 to 56.5±4.6 mmHg, p=0.038), and its change from baseline was associated with a larger increment in FEGlu (r=0.48, p=0.003. In conclusion, SGLT2i effects on renal glucose reabsorption are consistent across the spectrum of glucose tolerance. Moreover, FEGlu is a function of ambient hyperglycemia and, to a lesser extent, insulinemia. Finally, in T1D, decrements in renal hyperfiltration are related to greater glycosuria, possibly as a function of natriuresis. Disclosure Y. Lytvyn: None. A. Lytvyn: None. E.O. Muscelli: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. E. Ferrannini: None.
Background: increasing reports suggest that morbid obesity (BMI ≥ 40 kg/m2) is associated with an... more Background: increasing reports suggest that morbid obesity (BMI ≥ 40 kg/m2) is associated with an early impairment of intrinsic myocardial function, possibly contributing to an increased susceptibility to heart failure. However, the relative role of obesity and associated comorbidities such as HBP and diabetes in LV dysfunction is still unclear. Aim of the study: to investigate subclinical cardiovascular involvement in patients with isolated morbid obesity as compared to age-matched lean subjects. Methods: 38 lean healthy volunteers (BMI ≤ 25 kg/m2, 21 females, mean age 39 ± 11, BP 118 ± 9/69 ± 8 mmHg) and 29 non diabetic normotensive patients with morbid obesity (24 females, mean age 34 ± 10, BP 123 ± 10/78 ± 9 mmHg) were studied. LV geometry, pump function, midwall circumferential shortening, diastolic filling, myocardial longitudinal systolic and diastolic velocities, were evaluated by 2-D and M-mode echo, transmitral Doppler and Tissue Doppler Imaging of mitral annulus and interventricular septum and lateral wall (Aloka SSD-5500). Indices of aortic stiffness and arterial wave reflection were obtained by carotid-femoral pulse wave velocity (PWV) and carotid augmentation index (AIx). Ratio of stroke volume to pulse pressure (SV/PP) was used as an index of total arterial compliance Results: Compared to lean subjects, obese patients had significantly (p < at least 0.05) higher HR (75 ± 10 vs 62 ± 9 bpm), LV diastolic diameter (5.5 ± 0.7 vs 5.0 ± 0.5 cm), LV mean wall thickness (0.85 ± 0.11 vs 0.73 ± 0.13), LVMI (51 ± 15 vs 34 ± 9 g/m2.7), cardiac output (6.9 ± 2.5 vs 4.9 ± 1.1 L), LV stroke work (160 ± 50 vs 135 ± 34 g-ml/beat), mitral A velocity (0.63 ± 0.14 vs 0.52 ± 0.12 m/s), E/Ea ratio (a Doppler index related to capillary pulmonary pressure: 6.6 ± 4.4 vs 4.5 ± 1.1) and SV/PP (2.0 ± 0.6 vs 1.6 ± 0.4 ml/mmHg). Total peripheral resistance was significantly lower (1199 ± 419 vs 1452 ± 360 dyn*s/cm5). No differences between groups were found for LV midwall systolic shortening, longitudinal myocardial velocities, PWV and AIx. Conclusion: young to middle age patients with morbid obesity still free of comorbidities show an hyperdynamic circulatory state associated to volume overload, without detectable subclinical abnormalities of intrinsic myocardial function and arterial function.
To determine the possible existence of a relationship between insulin resistance and sympathetic ... more To determine the possible existence of a relationship between insulin resistance and sympathetic nervous system activity in essential hypertension, we calculated the double cross index for 14 hypertensive subjects and 14 normotensive subjects submitted to the oral glucose test. Plasma glucose and insulin levels were similar in hypertensive and normotensive subjects. After glucose loading, however, both parameters were significantly higher in hypertensive subjects. Five out of 14 hypertensive patients were hyperinsulinemic. The increase in double cross index following a glucose load was significantly higher in normotensive volunteers than in hyperinsulinemic hypertensive subjects. No change in double cross index was observed in normoinsulinemic hypertensive subjects. Thus, insulin resistance, high blood glucose level, impairment of cardiac response and hyperinsulinemia are present in a significant portion of hypertensive patients. Hyperinsulinemia may contribute to hypertension by stimulating sympathetic nervous system activity, by influencing the calcium transport across the cell membrane and/or by some other mechanism.
The Journal of Clinical Endocrinology and Metabolism, Apr 9, 2022
Context Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia an... more Context Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. Objective To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. Methods PubMed, Scopus, and Web-of-Science were searched. Studies measuring IE by the gold-standard protocol employing an oral glucose tolerance test (OGTT) and an intravenous glucose infusion at matched glucose levels were selected. We extracted IE, sex, age, body mass index (BMI), and hemoglobin A1c, fasting values, and area under curve (AUC) of glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). In subjects with T2D, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. Results The IE weighted mean difference between subjects with T2D and those with normal glucose tolerance (NGT) was −27.3% (CI –36.5% to –18.1%; P < .001; I2 = 86.6%) and was affected by age (P < .005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (P < .05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (P < .0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI 9.2-13.2%; P < .0001; I2 = 28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. Conclusion The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in subjects with T2D only, the OGTT dose is a significant covariate.
The metabolic and hemodynamic correlates of SGLT2i-mediated UGE in patients with diabetes are not... more The metabolic and hemodynamic correlates of SGLT2i-mediated UGE in patients with diabetes are not well understood. Accordingly, in this post hoc analysis, we measured UGE in 66 T2D, 37 T1D, and 25 nondiabetic (ND) participants under baseline conditions and following treatment with an SGLT2i (empagliflozin, 25 mg/d, EMPA). Measurements were taken during 3 h of fasting and 5 h of a mixed meal absorption (T2D and ND) or under usual clinical conditions in patients with T1D. Fractional glucose excretion (FEGlu) was obtained as the ratio of UGE to the filtered glucose load (=GFR x plasma glucose concentration [G]). In T1D participants only, ERPFPAH and GFRINULIN were measured and intraglomerular pressure (PGLO) estimated. With EMPA, FEGlu was 38±12% and 46±11% in T2D (fasting and post meal, respectively), 26±11% and 36±8% in ND, and 45±21% in T1D. In the pooled T1D, T2D and ND cohort, overall effect of EMPA on FEGlu was 39±11%; in this model, [G] was a positive determinant (FEGlu=34% at a [G] of 100 mg/dL and 44% at a [G] of 200 mg/dL, r=0.38, p<0.0001), whereas presence of T1D, T2D or ND was not. After adjusting for [G], plasma insulin concentration was also a positive determinant of FeGlu (r=0.12, p=0.01), adding 3% to FEGlu at the mean post meal plasma insulin of 50 µU/mL in T2D and ND; likewise, in T1D, FEGlu was related to the mean daily insulin dose (r=0.41, p<0.01). As described in previous work, in T1D, EMPA decreased ERPF and increased renal vascular resistance (p<0.01). Estimated PGLO was reduced (59.0±6.7 to 56.5±4.6 mmHg, p=0.038), and its change from baseline was associated with a larger increment in FEGlu (r=0.48, p=0.003. In conclusion, SGLT2i effects on renal glucose reabsorption are consistent across the spectrum of glucose tolerance. Moreover, FEGlu is a function of ambient hyperglycemia and, to a lesser extent, insulinemia. Finally, in T1D, decrements in renal hyperfiltration are related to greater glycosuria, possibly as a function of natriuresis. Disclosure Y. Lytvyn: None. A. Lytvyn: None. E.O. Muscelli: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. E. Ferrannini: None.
Background: increasing reports suggest that morbid obesity (BMI ≥ 40 kg/m2) is associated with an... more Background: increasing reports suggest that morbid obesity (BMI ≥ 40 kg/m2) is associated with an early impairment of intrinsic myocardial function, possibly contributing to an increased susceptibility to heart failure. However, the relative role of obesity and associated comorbidities such as HBP and diabetes in LV dysfunction is still unclear. Aim of the study: to investigate subclinical cardiovascular involvement in patients with isolated morbid obesity as compared to age-matched lean subjects. Methods: 38 lean healthy volunteers (BMI ≤ 25 kg/m2, 21 females, mean age 39 ± 11, BP 118 ± 9/69 ± 8 mmHg) and 29 non diabetic normotensive patients with morbid obesity (24 females, mean age 34 ± 10, BP 123 ± 10/78 ± 9 mmHg) were studied. LV geometry, pump function, midwall circumferential shortening, diastolic filling, myocardial longitudinal systolic and diastolic velocities, were evaluated by 2-D and M-mode echo, transmitral Doppler and Tissue Doppler Imaging of mitral annulus and interventricular septum and lateral wall (Aloka SSD-5500). Indices of aortic stiffness and arterial wave reflection were obtained by carotid-femoral pulse wave velocity (PWV) and carotid augmentation index (AIx). Ratio of stroke volume to pulse pressure (SV/PP) was used as an index of total arterial compliance Results: Compared to lean subjects, obese patients had significantly (p < at least 0.05) higher HR (75 ± 10 vs 62 ± 9 bpm), LV diastolic diameter (5.5 ± 0.7 vs 5.0 ± 0.5 cm), LV mean wall thickness (0.85 ± 0.11 vs 0.73 ± 0.13), LVMI (51 ± 15 vs 34 ± 9 g/m2.7), cardiac output (6.9 ± 2.5 vs 4.9 ± 1.1 L), LV stroke work (160 ± 50 vs 135 ± 34 g-ml/beat), mitral A velocity (0.63 ± 0.14 vs 0.52 ± 0.12 m/s), E/Ea ratio (a Doppler index related to capillary pulmonary pressure: 6.6 ± 4.4 vs 4.5 ± 1.1) and SV/PP (2.0 ± 0.6 vs 1.6 ± 0.4 ml/mmHg). Total peripheral resistance was significantly lower (1199 ± 419 vs 1452 ± 360 dyn*s/cm5). No differences between groups were found for LV midwall systolic shortening, longitudinal myocardial velocities, PWV and AIx. Conclusion: young to middle age patients with morbid obesity still free of comorbidities show an hyperdynamic circulatory state associated to volume overload, without detectable subclinical abnormalities of intrinsic myocardial function and arterial function.
To determine the possible existence of a relationship between insulin resistance and sympathetic ... more To determine the possible existence of a relationship between insulin resistance and sympathetic nervous system activity in essential hypertension, we calculated the double cross index for 14 hypertensive subjects and 14 normotensive subjects submitted to the oral glucose test. Plasma glucose and insulin levels were similar in hypertensive and normotensive subjects. After glucose loading, however, both parameters were significantly higher in hypertensive subjects. Five out of 14 hypertensive patients were hyperinsulinemic. The increase in double cross index following a glucose load was significantly higher in normotensive volunteers than in hyperinsulinemic hypertensive subjects. No change in double cross index was observed in normoinsulinemic hypertensive subjects. Thus, insulin resistance, high blood glucose level, impairment of cardiac response and hyperinsulinemia are present in a significant portion of hypertensive patients. Hyperinsulinemia may contribute to hypertension by stimulating sympathetic nervous system activity, by influencing the calcium transport across the cell membrane and/or by some other mechanism.
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