Validating and Establishing a Diagnostic Threshold for the Hypoglycemia Awareness Questionnaire Impaired Awareness Subscale.

OBJECTIVE: To evaluate the discriminant and convergent validities of the Hypoglycemia Awareness Questionnaire Impaired Awareness (HypoA-Q IA) subscale and establish a diagnostic threshold for the classification of impaired awareness of hypoglycemia (IAH) in adults with type 1 diabetes (T1D). METHODS: Twenty-one adults with T1D (male, 48%; median age, 36 years; and T1D duration, 21 years) completed the HypoA-Q IA subscale, Clarke, and hypoglycemia severity (HYPO) scores, continuous glucose monitoring, and hyperinsulinemic hypoglycemic clamp testing. Those with IAH defined by a Clarke score of ≥4 (n = 10) and who experienced severely problematic hypoglycemia and/or marked glycemic lability started automated insulin delivery as part of an 18-month intervention study with the 6-monthly paired assessment of the HypoA-Q IA subscale, Clarke score, HYPO score and continuous glucose monitoring, and hypoglycemic clamp testing at baseline and 6 and 18 months. RESULTS: The HypoA-Q IA subscale discriminated between those with and without IAH defined by the Clarke score (W = 110.5; P <.001). During intervention, the HypoA-Q IA subscale demonstrated convergent validity via significant relationships with the Clarke (r = 0.72; P <.001) and HYPO (r = 0.60; P <.001) scores; hypoglycemia exposure below 70 (r = 0.53; P <.01), 60 (r = 0.50; P <.01), and 54 (r = 0.48; P <.01) mg/dL; and autonomic symptom (r = -0.53; P <.05), epinephrine (r = -0.68; P <.001), and pancreatic polypeptide (r = -0.52; P <.05) responses to insulin-induced hypoglycemia. The receiver operating characteristic curve analysis revealed that the HypoA-Q IA subscale was an excellent predictor of an abnormal symptom response to insulin-induced hypoglycemia (area under the curve, 0.86) with a score of 12, which was the optimal threshold for IAH classification (sensitivity, 83%; specificity, 80%). CONCLUSION: These findings support the validity of the HypoA-Q IA subscale and propose a HypoA-Q IA diagnostic threshold to identify IAH in both clinical and research settings.

Preservation of ß-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

CONTEXT: Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). OBJECTIVE: This longitudinal case-control study assessed changes in ß-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). METHODS: Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. RESULTS: Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. CONCLUSION: ETI preserves ß-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

Automated Insulin Delivery for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes with Hypoglycemia Unawareness.

Objective: Automated insulin delivery (AID) may benefit individuals with long-standing type 1 diabetes where frequent exposure to hypoglycemia impairs counterregulatory responses. This study assessed the effect of 18 months AID on hypoglycemia avoidance and glucose counterregulatory responses to insulin-induced hypoglycemia in long-standing type 1 diabetes complicated by impaired awareness of hypoglycemia. Methods: Ten participants mean ± standard deviation age 49 ± 16 and diabetes duration 34 ± 16 years were initiated on AID. Continuous glucose monitoring was paired with actigraphy to assess awake- and sleep-associated hypoglycemia exposure every 3 months. Hyperinsulinemic hypoglycemic clamp experiments were performed at baseline, 6, and 18 months postintervention. Hypoglycemia exposure was reduced by 3 months, especially during sleep, with effects sustained through 18 months (P ≤ 0.001) together with reduced glucose variability (P < 0.01). Results: Hypoglycemia awareness and severity scores improved (P < 0.01) with severe hypoglycemia events reduced from median (interquartile range) 3 (3-10) at baseline to 0 (0-1) events/person·year postintervention (P = 0.005). During the hypoglycemic clamp experiments, no change was seen in the endogenous glucose production (EGP) response, however, peripheral glucose utilization during hypoglycemia was reduced following intervention [pre: 4.6 ± 0.4, 6 months: 3.8 ± 0.5, 18 months: 3.4 ± 0.3 mg/(kg·min), P < 0.05]. There were increases over time in pancreatic polypeptide (Pre:62 ± 29, 6 months:127 ± 44, 18 months:176 ± 58 pmol/L, P < 0.01), epinephrine (Pre: 199 ± 53, 6 months: 332 ± 91, 18 months: 386 ± 95 pg/mL, P = 0.001), and autonomic symptom (Pre: 6 ± 2, 6 months: 6 ± 2, 18 months: 10 ± 2, P < 0.05) responses. Conclusions: AID led to a sustained reduction of hypoglycemia exposure. EGP in response to insulin-induced hypoglycemia remained defective, however, partial recovery of glucose counterregulation was evidenced by a reduction in peripheral glucose utilization likely mediated by increased epinephrine secretion and, together with improved autonomic symptoms, may contribute to the observed clinical reduction in hypoglycemia.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Type 1 diabetes patients increase CXCR4+ and CXCR7+ haematopoietic and endothelial progenitor cells with exercise, but the response is attenuated.

Exercise mobilizes angiogenic cells, which stimulate vascular repair. However, limited research suggests exercise-induced increase of endothelial progenitor cell (EPCs) is completely lacking in type 1 diabetes (T1D). Clarification, along with investigating how T1D influences exercise-induced increases of other angiogenic cells (hematopoietic progenitor cells; HPCs) and cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), is needed. Thirty T1D patients and 30 matched non-diabetes controls completed 45 min of incline walking. Circulating HPCs (CD34+, CD34+CD45dim) and EPCs (CD34+VEGFR2+, CD34+CD45dimVEGFR2+), and subsequent expression of CXCR4 and CXCR7, were enumerated by flow cytometry at rest and post-exercise. Counts of HPCs, EPCs and expression of CXCR4 and CXCR7 were significantly lower at rest in the T1D group. In both groups, exercise increased circulating angiogenic cells. However, increases was largely attenuated in the T1D group, up to 55% lower, with CD34+ (331 ± 437 Δcells/mL vs. 734 ± 876 Δcells/mL p = 0.048), CD34+VEGFR2+ (171 ± 342 Δcells/mL vs. 303 ± 267 Δcells/mL, p = 0.006) and CD34+VEGFR2+CXCR4+ (126 ± 242 Δcells/mL vs. 218 ± 217 Δcells/mL, p = 0.040) significantly lower. Exercise-induced increases of angiogenic cells is possible in T1D patients, albeit attenuated compared to controls. Decreased mobilization likely results in reduced migration to, and repair of, vascular damage, potentially limiting the cardiovascular benefits of exercise.Trial registration: ISRCTN63739203.

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

Characterization and biological actions of N-terminal truncated forms of glucose-dependent insulinotropic polypeptide.

The N-terminal domain of glucose-dependent insulinotropic polypeptide (GIP) plays an important role in regulating biological activity. This study examined biological properties of several N-terminal truncated forms of GIP and two novel forms with substitutions at Phe position-6 with Arg or Val. GIP(6-42), GIP(R6-42), GIP(V6-42), GIP(7-42) and GIP(9-42) stimulated cAMP production in BRIN-BD11 cells similar to native GIP, whereas responses to GIP(3-42), GIP(4-42), GIP(5-42) and GIP(8-42) were reduced (P<0.01 to P<0.001). GIP-induced cyclic AMP production was significantly inhibited by GIP(3-42), GIP(4-42), GIP(5-42), GIP(6-42), GIP(R6-42), GIP(7-42) and GIP(8-42) (P<0.001). Compared with native GIP, in vitro insulinotropic activity of GIP(3-42), GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) was reduced (P<0.05 to P<0.001), with GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) also potently inhibiting GIP-stimulated insulin secretion (P<0.001). In ob/ob mice, GIP(4-42) and GIP(8-42) increased (P<0.05 to P<0.01) plasma glucose concentrations compared to the glucose-lowering action of native GIP. When GIP(8-42) was co-administered with native GIP it countered the ability of the native peptide to lower plasma glucose and increase circulating insulin concentrations. These data confirm the importance of the N-terminal region of GIP in regulating bioactivity and reveal that sequential truncation of the peptide yields novel GIP receptor antagonists which may have functional significance.