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Papers by James Shaw

Diabetes, Jun 20, 2023

Aims: Postprandial glucose excursions contribute to dysglycemia in type 1 diabetes (T1D). Hypergl... more Aims: Postprandial glucose excursions contribute to dysglycemia in type 1 diabetes (T1D). Hyperglucagonaemia may play a role but the relationship between beta and alpha-cell dysfunction together with incretin response remains unclear. We sought to elucidate this in people with established T1D with and without C-peptide. Methods: Participants (n=29, age 38 ± 12 years, HbA1c 57 ± 9 mmol/mol, T1D duration 20 ± 13 years) with a range of postprandial urine C-peptide were recruited. A Meal Tolerance Test (MTT, 240 mL Fortisip: 360kcal, 14.4g protein, 13.92g fat, 44.16g carbohydrate) was completed after an overnight fast, maintaining normal basal insulin, without an insulin bolus. Blood samples were taken pre and 30min intervals for 180 minutes post-drink and analysed for glucose, C-peptide, glucagon, proinsulin, GLP-1 and GIP. Participants were grouped by peak C-peptide (high >200 pmol/L, low 3-200pmol/L, undetectable). [Incremental] area under the curves ([i]AUC) were compared by one way ANOVA, Spearman's correlation and multiple regression with significance accepted p≤0.05. Results: Ten participants had high peak C-peptide (680 ± 426 pmol/L), 8 low (39 ± 34 pmol/L), and 11 undetectable. Glucagon was comparable in all groups with mean AUC 1721 ± 890 pmol/L*180min (p=0.84). Glucagon correlated with GLP-1 (r=0.81, p<0.01) and GIP (r=0.43, p=0.02) response, but not C-peptide (R=-0.10, p=0.61), proinsulin (r=-0.18, p=0.35) or proinsulin/C-peptide ratio (r=0.04, p=0.85). C-peptide predicted glucose AUC using multiple regression (R2 = 44.3%, F(1, 27) = 21.4, p<0.01). C-peptide in combination with glucagon predicted glucose iAUC (R2 = 41.1% F(2, 26) = 9.1, p<0.01). Conclusion: Residual C-peptide is a predictor of MTT glucose excursions but not glucagon response in established T1D. Postprandial glucagon contributed to glucose excursion as well as correlating with incretin response. This supports altered alpha-cell phenotype in T1D, aberrantly responding to or secreting incretin. Disclosure G.Taylor: None. K.Smith: None. A.Bashir: None. T.J.Mcdonald: None. E.J.Stevenson: None. J.A.Shaw: Advisory Panel; Betalin Therapeutics, Provention Bio, Inc., Consultant; Mogrify. D.J.West: None. Funding Diabetes Research and Wellness Foundation (SCA/OF/12/15); Francis James Bell Endowment Fund; Country Durham Community Foundation

Biochemical Society Transactions, 2008

Defective insulin secretion is a hallmark of all forms of diabetes. Whereas Type 1 diabetes has l... more Defective insulin secretion is a hallmark of all forms of diabetes. Whereas Type 1 diabetes has long been known to result from the immune-mediated destruction of β-cells, Type 2 diabetes appears to involve both loss of β-cell mass and glucose sensitivity in the face of extrapancreatic insulin resistance. We summarize here the proceedings of a Biochemical Society Focused Meeting, held at the St Thomas campus of King's College London in December 2007, which highlighted recent research advances targeting the β-cell.

Cells

Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential com... more Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stim...

Cardiovascular Diabetology, 2015

Background Type 1 diabetes is associated with raised inflammation, impaired endothelial progenito... more Background Type 1 diabetes is associated with raised inflammation, impaired endothelial progenitor cell mobilisation and increased markers of vascular injury. Both acute and chronic exercise is known to influence these markers in non-diabetic controls, but limited data exists in Type 1 diabetes. We assessed inflammation, vascular repair and injury at rest and after exercise in physically-fit males with and without Type 1 diabetes. Methods Ten well-controlled type 1 diabetes (27 ± 2 years; BMI 24 ± 0.7 kg.m 2 ; HbA 1c 53.3 ± 2.4 mmol/mol) and nine non-diabetic control males (27 ± 1 years; BMI 23 ± 0.8 kg.m 2) matched for age, BMI and fitness completed 45-min of running. Venous blood samples were collected 60-min before and 60-min after exercise, and again on the following morning. Blood samples were processed for TNF-α using ELISA, and circulating endothelial progenitor cells (cEPCs; CD45 dim CD34 + VEGFR2 +) and endothelial cells (cECs; CD45 dim CD133-CD34 + CD144 +) counts using flow-cytometry. Results TNF-α concentrations were 4-fold higher at all-time points in Type 1 diabetes, when compared with control (P < 0.001). Resting cEPCs were similar between groups; after exercise there was a significant increase in controls (P = 0.016), but not in Type 1 diabetes (P = 0.202). CEPCs peaked the morning after exercise, with a greater change in controls vs. Type 1 diabetes (+139 % vs. 27 %; P = 0.01). CECs did not change with exercise and were similar between groups at all points (P > 0.05). Within the Type 1 diabetes group, the delta change in cEPCS from rest to the following morning was related to HbA 1c (r =-0.65, P = 0.021) and TNF-α (r =-0.766, P = 0.005). Conclusions Resting cEPCs and cECs in Type 1 diabetes patients with excellent HbA 1c and high physicalfitness are comparable to healthy controls, despite eliciting 4-fold greater TNF-α. Furthermore, Type 1 diabetes patients appear to have a blunted post-exercise cEPCs response (vascular repair), whilst a biomarker of vascular injury (cECs) remained comparable to healthy controls.

The American journal of clinical nutrition, 2015

Patients with type 1 diabetes face heightened risk of hypoglycemia after exercise. Subsequent ove... more Patients with type 1 diabetes face heightened risk of hypoglycemia after exercise. Subsequent overfeeding, as a preventative measure against hypoglycemia, negates the energy deficit after exercise. Patients are also required to reduce the insulin dose administered with postexercise foods to further combat hypoglycemia. However, the insulin dose is dictated solely by the carbohydrate content, even though postprandial glycemia is vastly influenced by glycemic index (GI). With a need to control the postexercise energy balance, appetite responses after meals differing in GI are of particular interest. We assessed the appetite response to low-glycemic index (LGI) and high-glycemic index (HGI) postexercise meals in type 1 diabetes patients. This assessment also offered us the opportunity to evaluate the influence of GI on appetite responses independently of insulinemia, which confounds findings in individuals without diabetes. Ten physically active men with type 1 diabetes completed 2 tri...

Diabetologia, 2009

Aims/hypothesis Type 1 diabetes is associated with premature arterial disease. Bone-marrow derive... more Aims/hypothesis Type 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased carotid intima-media thickness (CIMT). Methods We compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry. Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured. Results CD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46-69%; p=0.004-0.043). In people with type 1 diabetes, FMD was reduced by 45% (p<0.001) and CIMT increased by 25% (p<0.001), these being correlated (r=−0.25, p=0.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (r = 0.39, p = 0.001), CD133+VEGFR-2+ (r =0.25, p = 0.037) and CD34+ (r=0.34, p=0.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly higher in the diabetes group (p < 0.001 to p = 0.049), the last two of these correlating with FMD (r=−0.27, p=0.028 and r=−0.24, p=0.048, respectively). Conclusions/interpretation These findings suggest that abnormalities of endothelial function in addition to proinflammatory and pro-thrombotic states are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular events.

Diabetes Care, 2019

OBJECTIVE The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of ... more OBJECTIVE The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years’ follow-up. RESEARCH DESIGN AND METHODS A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 ...

Cell Medicine, 2011

Islet transplantation has become established as a successful treatment for type 1 diabetes compli... more Islet transplantation has become established as a successful treatment for type 1 diabetes complicated by recurrent severe hypoglycemia. In the UK access has been limited to a few centrally located units. Our goal was to validate a quality-assured system for safe/effective transport of human islets in the UK and to successfully undertake the first transplants with transported islets. Pancreases were retrieved from deceased donors in the north of England and transported to King's College London using two-layer method (TLM) or University of Wisconsin solution alone. Islets were isolated and transported back to Newcastle in standard blood transfusion or gas-permeable bags with detailed evaluation pre- and posttransport. In the preclinical phase, islets were isolated from 10 pancreases with mean yield of 258,000 islet equivalents. No significant differences were seen between TLM and University of Wisconsin solution organ preservation. A significant loss of integrity was demonstrated...

Diabetes Care, 2014

OBJECTIVE Islet graft function is defined by serum C-peptide in a standardized challenge test. We... more OBJECTIVE Islet graft function is defined by serum C-peptide in a standardized challenge test. We assessed whether urine C-peptide creatinine ratio (UCPCR) sent from home could provide a viable alternative. RESEARCH DESIGN AND METHODS Seventeen islet recipients provided 90-min serum C-peptide (sCP90) and 120-min UCPCR (UCPCR120) samples during 68 interval posttransplant mixed-meal tolerance tests, also posting from home a 120-min postbreakfast UCPCR sample every 2 weeks. UCPCR was compared with a clinical score of islet function, derived from HbA1c and insulin dose. RESULTS UCPCR120 and mean home postmeal UCPCR were strongly correlated with sCP90 (rs = 0.73, P < 0.001; and rs = 0.73, P < 0.01, respectively). Mean home UCPCR increased with clinical score (rs = 0.75; P < 0.001) and with graft function defined both by sCP90 >200 pmol/L and insulin independence. UCPCR cutoffs to detect insulin independence and poor graft function were sensitive and specific. CONCLUSIONS Home...

Diabetes care, 2014

To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglyc... more To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG). A 24-week 2 × 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score). A total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (≤3.0 mmol/L) decreased (53 ± 63 to 24 ± 56 min/24 h; P = 0.004 [t test]) without deterioration in HbA1c. Hypoglycemia awareness improved...

Diabetes Care

OBJECTIVE To investigate the impact of residual β-cell function on continuous glucose monitoring ... more OBJECTIVE To investigate the impact of residual β-cell function on continuous glucose monitoring (CGM) outcomes following acute exercise in people with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Thirty participants with T1D for ≥3 years were recruited. First, participants wore a blinded CGM unit for 7 days of free-living data capture. Second, a 3-h mixed-meal test assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund <3 pmol/L), low (Cpeplow 3–200 pmol/L), or high (Cpephigh >200 pmol/L) C-peptide groups. Finally, participants completed 45 min of incline treadmill walking at 60% VO2peak followed by a further 48-h CGM capture. RESULTS CGM parameters were comparable across groups during the free-living observation week. In the 12- and 24-h postexercise periods (12 h and 24 h), the Cpephigh group had a significantly greater amount of time spent with glucose 3.9–10 mmol/L (12 h, 73.5 ± 27.6%; 24 h, 76.3 ± 19....

Diabetes care, Aug 16, 2018

Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted pr... more Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care. Ninety-six adults with type 1 diabetes (29 ± 12 years' duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM v...

Diabetic Medicine

In the short term, continuous subcutaneous insulin infusion (CSII) has been associated with impro... more In the short term, continuous subcutaneous insulin infusion (CSII) has been associated with improved glycaemic control, reduced hypoglycaemia and improved quality of life (QOL). However, there limited data available on the long-term benefits. We aimed to assess the long-term impact of CSII use at Derby Teaching Hospitals on long term outcomes. Method: Patient-level data were obtained from the hospital electronic records for 258 CSII users at the Royal Derby Hospital. Patient-confidence and satisfaction questionnaires were sent by post. A likert scale was used to assess confidence in aspects of selfmanagement and quality of life. STATA v.13 was used for data analysis. Descriptive and comparative statistics were conducted to explore clinical outcomes using Pearson's Chi-square and student t-tests. Results: The mean age was 43.9 AE 13.4 years, baseline: HbA1c 9.2 AE 2.0%. There was a significant overall reduction in HbA1c from 9.3 AE 2.0% at baseline, to 8.5 AE 1.3% and 8.2 AE 1.3% at six month and six years respectively (mean diff:-0.87%; 95% CI:-1.12 to-0.61; p < 0.0001 at six years). Majority (75.6%) of the CSII users had a baseline HbA1c > 8.5%. This subgroup experienced greater reduction in HbA1c (mean diff:-1.39%; 95% CI:-1.66 to-1.11; p < 0.0001). A total pf 119 (46%) responded to the survey and 94.2% (114) reported an improved QOL; reduction in the frequency of hypoglycaemia (n = 95; 79.8%) and general satisfaction with the quality of care received in the insulin pump service (85.7%, n = 102). Conclusion: CSII therapy led to a sustained long-term improvement in glycaemic control in addition to improved quality of life and reduced self-reported hypoglycaemia in our centre.

SAGE open medicine, 2014

Severe hypoglycaemia affects approximately one in three people with type 1 diabetes and is the mo... more Severe hypoglycaemia affects approximately one in three people with type 1 diabetes and is the most serious side effect of insulin therapy. Our aim was to explore individualistic drivers of severe hypoglycaemia events. In-depth semi-structured interviews were conducted with a purposive sample of 17 adults with type 1 diabetes and a history of recurrent severe hypoglycaemia, to elicit experiences of hypoglycaemia (symptoms/awareness, progression from mild to severe and strategies for prevention/treatment). Interviews were analysed using an adapted grounded theory approach. Three main themes emerged: hypoglycaemia-induced cognitive impairment, behavioural factors and psychological factors. Despite experiencing early hypoglycaemic symptoms, individuals often delayed intervention due to impaired/distracted attention, inaccurate risk assessment, embarrassment, worry about rebound hyperglycaemia or unavailability of preferred glucose source. Delay coupled with use of a slow-acting glucose...

Journal of Endocrinology, 2002

The objective of these studies was to evaluate human insulin gene expression following intramuscu... more The objective of these studies was to evaluate human insulin gene expression following intramuscular plasmid injection in non-diabetic rats as a potential approach to gene therapy for diabetes mellitus avoiding the need for immunosuppression. A wild-type human preproinsulin construct and a mutant construct in which PC2/PC3 sites were engineered to form furin consensus sites were evaluated in in vitro transfections of hepatocyte (HepG2) and myoblast (C2C12/L6) cell lines, primary rat myoblasts, and dermal fibroblasts. In vivo gene transfer by percutaneous plasmid injection of soleus muscle +/- prior notexin-induced myolysis was assessed in rats. In vitro transfection of non-neuroendocrine cell lines and primary cultures with wild-type human preproinsulin resulted in secretion of predominantly unprocessed proinsulin. Employing the mutant construct, there was significant processing to mature insulin (HepG2, 95%; C2C12, 75%; L6, 65%; primary myoblasts, 48%; neonatal fibroblasts, 56%; ad...

The Journal of Clinical Endocrinology & Metabolism, 2010

Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, an... more Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, and possibly CV disease. However, its management remains controversial. Endothelial progenitor cells (EPC), expressing both endothelial and stem cell markers, are known to offer a novel CV risk marker. Objective: The aim of the study was to ascertain whether EPC count or function is reduced in SCH and whether it improves with T 4 therapy. Design and Intervention: EPC were studied in peripheral blood by fluorescence-activated cell sorter and following in vitro cultures before and after T 4 together with CV risk factors in 20 SCH and healthy controls (HC).