Berberine is an insulin secretagogue targeting the KCNH6 potassium channel

Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.

Precision and Accuracy of Hyperglycemic Clamps in a Multicenter Study

Background: Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Methods: Two- stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. Results: The RISE approach produced high overall precision (3-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD <10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs adult, IGT vs diabetes status) and to differences in physiology induced by study treatments. Conclusions: The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.

Insulin Resistance in Congenital Adrenal Hyperplasia is Compensated for by Reduced Insulin Clearance

Context Congenital adrenal hyperplasia (CAH) patients have potential normal longevity. However, a greater risk for cardiovascular disease has been reported. Insulin resistance and hyperinsulinemia have been described in CAH patients, whereas the prevalence of overt type 2 diabetes is not higher in CAH than in normal population. Objective To examine the contributions of insulin secretion and of hepatic insulin clearance to compensatory hyperinsulinemia in young insulin-resistant adults with classic CAH due to 21-hydroxylase deficiency (21-OHD). Design Cross-sectional. Setting University outpatient clinics. Methods Fifty-one participants: 21 controls, and 30 CAH (15 virilizing and 15 salt-wasting phenotypes), female/male (33/18), age (mean [SD]): 24.0 (3.6) years, body mass index: 24.6 (4.9)kg/m2 with normal glucose tolerance, were submitted to a hyperglycemic clamp study. Main Outcome Measures Insulin sensitivity, beta cell function, and hepatic insulin clearance using appropriate modeling. Results We found an increased insulin resistance in 21-OHD. The systemic hyperinsulinemia (posthepatic insulin delivery) was elevated in CAH patients. No increases were observed in insulin secretory rate (beta cell function) in the first phase or during the hyperglycemic clamp. The increase in insulin concentrations was totally due to a ~33% reduction in insulin clearance. Conclusion 21-OHD nonobese subjects have reduced insulin sensitivity and beta cell response unable to compensate for the insulin resistance, probably due to overexposure to glucocorticoids. Compensatory hyperinsulinemia is most related with reduced hepatic insulin clearance. The exclusive adaptation of the liver acts as a gating mechanism to regulate the access of insulin to insulin-sensitive tissues to maintain glucose homeostasis.

A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m²) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR_OGTT– AUC-SR_iso-IVGTT)/AUC-SR_OGTT[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m²) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR_OGTT– AUC-SR_iso-IVGTT)/AUC-SR_OGTT[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

<b>Background.</b> The risk genotype for the common variant <i>rs7903146 </i>of the transcription factor-7-like-2 gene (<i>TCF7L2</i>) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the <i>rs7903146</i> variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. <p><b>Methods</b> Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m²) were genotyped for the <i>rs7903146 </i>of <i>TCF7L2</i> and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation.</p> <p>The incretin effect was measured as 100*(AUC-SR_OGTT– AUC-SR_iso-IVGTT)/AUC-SR_OGTT[AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype.</p> <p><b>Results </b>The presence of T risk allele for <i>TCF7L2</i> was associated with a markedly reduced </p> <p>incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. </p> <p><b>Conclusion </b>A<b> </b> reduced incretin effect and its association with the <i>TCF7L2</i> variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal. </p>

Relative hypoxia and early diabetic kidney disease in type 1 diabetes

<a>The objective of this study was to compare the ratio of renal oxygen availability (RO₂) to GFR (RO₂:GFR), a measure of relative renal hypoxia, in adolescents with and without type 1 diabetes (T1D) and relate the ratio to albuminuria, renal plasma flow (RPF), fat mass, and insulin sensitivity (M/I). RO₂ was estimated by blood oxygenation level dependent (BOLD) MRI, fat mass by </a>DXA, GFR and RPF by iohexol and <i>p</i>-aminohippurate clearance, albuminuria by urine albumin-to-creatinine ratio (UACR), and M/I from steady-state glucose infusion rate/insulin (mg/kg/min) by hyperglycemic clamp in 50 adolescents with T1D (16.1±3.0 years, HbA1c 8.6±1.2%) and 20 controls of similar BMI (16.1±2.9 years, HbA1c 5.2±0.2%). <a>The RO₂:GFR (ms/ml/min) was calculated as renal oxygen availability (T2*, ms) divided by GFR (ml/min). </a>Whole-kidney RO₂:GFR was 25% lower in adolescents with T1D vs. controls (<i>p<</i>0.0001). In adolescents with T1D, lower whole-kidney RO₂:GFR associated with higher UACR (r=-0.31, <i>p</i>=0.03), RPF (r=-0.52, <i>p</i>=0.0009) and fat mass (r=-0.33, <i>p</i>=0.02). Lower medullary RO₂:GFR associated with lower M/I (r=0.31, <i>p</i>=0.03). In conclusion, adolescents with T1D exhibited relative renal hypoxia that associated with albuminuria, increased RPF, fat mass, and insulin resistance. These data suggest a potential role of renal hypoxia in the development of DKD.

Relative hypoxia and early diabetic kidney disease in type 1 diabetes

<a>The objective of this study was to compare the ratio of renal oxygen availability (RO₂) to GFR (RO₂:GFR), a measure of relative renal hypoxia, in adolescents with and without type 1 diabetes (T1D) and relate the ratio to albuminuria, renal plasma flow (RPF), fat mass, and insulin sensitivity (M/I). RO₂ was estimated by blood oxygenation level dependent (BOLD) MRI, fat mass by </a>DXA, GFR and RPF by iohexol and <i>p</i>-aminohippurate clearance, albuminuria by urine albumin-to-creatinine ratio (UACR), and M/I from steady-state glucose infusion rate/insulin (mg/kg/min) by hyperglycemic clamp in 50 adolescents with T1D (16.1±3.0 years, HbA1c 8.6±1.2%) and 20 controls of similar BMI (16.1±2.9 years, HbA1c 5.2±0.2%). <a>The RO₂:GFR (ms/ml/min) was calculated as renal oxygen availability (T2*, ms) divided by GFR (ml/min). </a>Whole-kidney RO₂:GFR was 25% lower in adolescents with T1D vs. controls (<i>p<</i>0.0001). In adolescents with T1D, lower whole-kidney RO₂:GFR associated with higher UACR (r=-0.31, <i>p</i>=0.03), RPF (r=-0.52, <i>p</i>=0.0009) and fat mass (r=-0.33, <i>p</i>=0.02). Lower medullary RO₂:GFR associated with lower M/I (r=0.31, <i>p</i>=0.03). In conclusion, adolescents with T1D exhibited relative renal hypoxia that associated with albuminuria, increased RPF, fat mass, and insulin resistance. These data suggest a potential role of renal hypoxia in the development of DKD.