Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets

Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E)22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P)14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid), a non-metabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared to P14 β-cells. The investigation of electrophysiological characteristics of dispersed β-cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

Postnatal activation of hypoxia pathway disrupts β-cell functional maturation

Objective: Hypoxic injuries occurring during the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of hypoxia-inducible pathway on the postnatal beta-cell function. Methods: Rat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor 1A (HIF1A). In parallel, mouse pups were placed in a hypoxic chamber between embryonic day (E)19 to P6. Dynamic insulin secretion was assessed in both models by islet perifusions. Changes in gene expression were assessed by whole-islet RNA sequencing. Results: AQ-treated rat pups and hypoxic mouse pups were hypoglycemic and had higher levels of serum insulin. The AQ-/hypoxia-treated islets showed a decreased glucose threshold for insulin secretion compared to controls, indicative of a delay in beta-cell postnatal functional maturation. Islet morphometric analysis in the AQ-treated pups showed an increase in insulin area per pancreas, but no change in the number of islets or in the number of beta-cells per islet, consistent with a higher average size of beta-cells. Differential transcriptomic analysis showed upregulation of the expected HIF1A target genes. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating beta;-cells. Conclusion: We showed that hypoxia and pharmacologic activation of the hypoxia inducible pathway in early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion. This exaggerated activation of hypoxia pathway also decreased early postnatal beta-cell proliferation, suggesting it can impact adult beta-cell mass and diabetes risk.

Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion in the early postnatal period

Objective: Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We hypothesized that this transitional hyperinsulinism is due to the persistence of a fetal lower glucose threshold for insulin release from β-cells into the first postnatal days. Methods: We tested dynamic insulin secretion from freshly isolated rat islets between late gestation and adult age and from rat islets kept in culture for 1 or 2 days. We used single-cell transcriptomic and electrophysiology approaches to investigate the mechanism for insulin secretion at low glucose concentrations. Results: We found that a lower threshold for glucose-stimulated insulin secretion (GSIS) is present in embryonic day (E)22 islets and persists into the first postnatal days. The glucose threshold increases in the postnatal period and reaches the adult level by postnatal day (P)14. We also demonstrated that culturing P14 islets for 24-48 hrs can also decrease the glucose threshold. Insulin release in response to BCH, a non-metabolizable leucine analog activating glutamate dehydrogenase, had a similar lower threshold in P1 compared to P14 islets. This showed that the low threshold for GSIS is determined at a step downstream of the glycolytic pathway. P1 islets had lower insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels, compared to P14 islets, suggesting that decreased KATP channel expression and/or function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal differences in transcripts between E22 and P14 β-cells supporting the lower glucose threshold. The investigation of electrophysiological characteristics of dispersed β cells showed that early neonatal cells and cultured islet cells had fewer functional KATP channels per unit membrane area. Conclusion: These findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

Metabolic characteristics of Africans with normal glucose tolerance and elevated 1-hour glucose: insight from the Africans in America study

IntroductionRisk of insulin resistance, dyslipidemia, diabetes and cardiac death is increased in Asians and Europeans with normal glucose tolerance (NGT) and 1-hour glucose ≥8.6 mmol/L. As African descent populations often have insulin resistance but a normal lipid profile, the implications for Africans with NGT and glucose ≥8.6 mmol/L (NGT-1-hour-high) are unknown.ObjectiveWe performed oral glucose tolerance tests (OGTTs) in 434 African born-blacks living in Washington, DC (male: 66%, age 38±10 years (mean±SD)) and determined in the NGT group if either glucometabolic or lipid profiles varied according to a 1-hour-glucose threshold of 8.6 mmol/L.MethodsGlucose tolerance category was defined by OGTT criteria. NGT was subdivided into NGT-1-hour-high (glucose ≥8.6 mmol/L) and NGT-1-hour-normal (glucose <8.6 mmol/L). Second OGTT were performed in 27% (119/434) of participants 10±7 days after the first. Matsuda Index and Oral Disposition Index measured insulin resistance and beta-cell function, respectively. Lipid profiles were obtained. Comparisons were by one-way analysis of variance with Bonferonni corrections for multiple comparisons. Duplicate tests were assessed by к-statistic.ResultsOne-hour-glucose ≥8.6 mmol/L occurred in 17% (47/272) with NGT, 72% (97/134) with pre-diabetes and in 96% (27/28) with diabetes. Both insulin resistance and beta-cell function were worse in NGT-1-hour-high than in NGT-1-hour-normal. Dyslipidemia occurred in both the diabetes and pre-diabetes groups but not in either NGT group. One-hour glucose concentration ≥8.6 mmol/L showed substantial agreement for the two OGTTs (к=0.628).ConclusionsAlthough dyslipidemia did not occur in either NGT group, insulin resistance and beta-cell compromise were worse in NGT-1 hour-high. Subdividing the NGT group at a 1-hour glucose threshold of 8.6 mmol/L may stratify risk for diabetes in Africans.

DETERMINATION OF INDIVIDUAL GLUCOSE THRESHOLD USING PHARMACY PORTABLE BLOOD GLUCOSE METER

ABSTRACT Introduction The individual glucose threshold (IGT) has been used to estimate the anaerobic threshold with low-cost analyses and shorter times. However, the reliability of the glycemic analysis using a portable pharmacy glucose meter has received little attention. Objective To identify the IGT using a portable glucose meter and to compare it with the ventilatory threshold (VT). Methods Fourteen active, healthy men (25.9 ± 3.2 years; %BF = 17.9 ± 3.7%) performed an incremental treadmill test. The anaerobic threshold was identified by two different methods: (1) IGT, corresponding to the intensity of the lowest glucose value during the test; and (2) VT, corresponding to the break in linearity of the ventilation curve and an increase in the respiratory oxygen equivalent, without an equivalent increase in carbon dioxide. Results There were significant differences between VT (9.9 ± 1.2 km/h) and IGT (9.5 ± 1/1 km/h), corresponding to 75.4 ± 9.2 and 72.5 ± 10.4 %VO2max, respectively. The methods presented high correlation (r = 0.82, p = 0.002) and the Bland-Altman technique showed agreement between IGT and VT, with a mean difference of 0.5 km/h. Conclusion It was possible to determine the intensity of IGT by the glycemic response in the incremental test using a portable glucose meter. The IGT underestimated the intensity of VT by approximately 0.5 km/h, but with a high correlation and agreement between them. Level of evidence III, Case-Controle Study.

World diabetes day 2017 focus: antepartum hyperglycaemia (or gestational prediabetes) is more in women below 40 years

Prediabetes is a state of hyperglycaemia that is above normal, but below blood glucose threshold for diabetes mellitus. As part of the theme for World Diabetes Day of 2017, it has been articulated by the International Diabetes Federation, that up to 16% of births may be affected by this condition and it is estimated that 50% of the affected antenatal patients are under 30 years old. The notion of gestational prediabetes, hyperglycaemia in pregnancy as a clinical condition is yet to be seriously discussed in regards to prediabetes in pregnancy. Instead, it seems to be subsumed in the discourse of gestational diabetes mellitus. This subsuming position is evident in the fact that even in discussion of management challenges of the ‘hyperglycaemia in pregnancy’ condition, blood glucose thresholds for gestational diabetes refers to higher versus lower cut-offs, but never refers to prediabetes.