Richard M. Smith

Risk Factors for Diabetes and Cardiovascular Disease in Young Australian Aborigines: A 5-year follow-up study

OBJECTIVE To test the hypothesis that hyperinsulinemia and glucose intolerance are present at an early age in australian aborigines and can be used to predict the eventual development of NIDDM. RESEARCH DESIGN AND METHODS Baseline anthropometric, pubertal stage, and blood pressure data were collected for 100 Australian aboriginal children and adolescents in 1989. Plasma concentrations of glucose, insulin, C-peptide, triglycerides, and LDL, HDL, and total cholesterol were measured before and during an oral glucose tolerance test. All measurements were repeated in 74 individuals from the original study population in 1994. Results were compared among hyperinsulinemic and normoinsulinemic subjects, and subjects with normal or abnormal glucose tolerance. RESULTS The percentage of subjects who were overweight increased from 2.7% at baseline to 17.6% 5 years later. At a mean age of 18.5 years, 8.1% of the population had impaired glucose tolerance (IGT), 2.7% had diabetes, and 21.6% had elevated cholesterol concentrations in plasma. Dyslipidemia was particularly prevalent among male subjects in the population: 34.4% had elevated plasma cholesterol and 21.9% had elevated LDL cholesterol values. Of the eight subjects who had diabetes or IGT in 1994, four were classified as hyperinsulinemic in 1989 and four were not. CONCLUSIONS The major finding of this study is the high prevalence of risk factors for NIDDM and cardiovascular disease in this population of aboriginal children and adolescents. Abnormalities of carbohydrate and lipid metabolism were well established by late in the second decade of life. Although many subjects had high insulin levels and there was evidence of insulin resistance in the population, hyperinsulinemia did not predict the development of abnormal glucose tolerance 5 years later.

Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes.

OBJECTIVE Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide–positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes. RESULTS A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6–3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients). CONCLUSIONS This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing.

Pancreatic islet xenotransplantation: the potential for tolerance induction

Abstract Pancreatic islet transplantation can correct the disordered glucose metabolism of IDDM, but its widespread application will probably need a non-human source of islets. Immunosuppression presently available to control rejection of xenografts is unsustainable clinically. However, experiments in rodents suggest that xenogeneic islets can survive without continuing immunosuppression and experiments in large outbred species suggest that clinically applicable protocols are possible.

Birthweights and growth of infants in five Aboriginal communities

Objectives : To improve, by culturally appropriate means, birthweights and growth of children up to three years of age over 14 months in five Aboriginal communities in north‐western Australia.

Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UKs nationally funded integrated islet transplant program. Twenty islet recipients with C‐peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5–36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7–50) episodes/patient‐year pretransplant to 0.3 (0–1.6) episodes/patient‐year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5–7); 24 (13.5–36) months: 3 (1.5–4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0–9.6)%; 24 (13.5–36) months: 6.2 (5.7–8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41–0.62) units/kg; 24 (13.5–36) months: 0.20 (0–0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C‐peptide: transported 788 (114–1764) pmol/L (n = 9); locally isolated 407 (126–830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Transplantation treatment for diabetes

Islet transplantation in the treatment of insulin-dependent diabetes mellitus is making rapid progress. Vascularized pancreas allotransplantation is now an accepted treatment but has major limitations. A recent meeting∗ discussed alternative approaches, particularly islet xenotransplantation.

CD86 Has Sustained Costimulatory Effects on CD8 T Cells

CD80 and CD86 both costimulate T cell activation. Their individual effects in vivo are difficult to study as they are coordinately up-regulated on APCs. We have studied mice expressing rat insulin promoter (RIP)-CD80 and RIP-CD86 on the NOD and NOD.scid genetic background to generate in vivo models, using diabetes as a readout for cytotoxic T cell activation. Accelerated spontaneous diabetes onset was observed in NOD-RIP-CD80 mice and the transfer of diabetes from 6-wk-old NOD mice to NOD.scid-RIP-CD80 mice was greater compared with NOD-RIP-CD86 and NOD.scid-RIP-CD86 mice, respectively. However, the secondary in vivo response was maintained if T cells were activated through CD86 costimulation compared with CD80. This was demonstrated by greater ability to cause recurrent diabetes in NOD-RIP-CD86 diabetic mice transplanted with 6-wk-old NOD islets and adoptively transferred diabetes from diabetic NOD-RIP-CD86 mice to NOD.scid mice. In vitro, CD80 costimulation enhanced cytotoxicity, proliferation, and cytokine secretion in activated CD8 T cells compared with CD86 costimulation. We demonstrated increased CTLA-4 and programmed death-1 inhibitory molecule expression following costimulation by both CD80 and CD86 (CD80 > CD86). Furthermore, T cells stimulated by CD80 were more susceptible to inhibition by CD4+CD25+ T cells. Overall, while CD86 does not stimulate an initial response as strongly as CD80, there is greater sustained activity that is seen even in the absence of continued costimulation. These functions have implications for the engineered use of costimulatory molecules in altering immune responses in a therapeutic setting.

Renal function in type 1 diabetics one year after successful pancreas transplantation.

Chatzizacharias NA, Vaidya A, Sinha S, Smith R, Jones G, Sharples E, Friend PJ. Renal function in type 1 diabetics one year after successful pancreas transplantation.
Clin Transplant 2011: 25: E509–E515.

A “fussy eater” with renal failure

In May, 2009, a 17-year-old girl was admitted with a 10-day history of anorexia and vomiting. She had no signifi cant medical or family history, and was on no medication other than the oral contraceptive pill. Examination was unremarkable, with normal blood pressure and volume status. She had severe non-oliguric renal impairment (urea 64 mmol/L, creatinine 1596 μmol/L). Urinalysis showed haematuria and proteinuria. Full blood count showed macrocytic anaemia (haemoglobin 88 g/L, MCV 116 fL); blood fi lm showed hypersegmented neutrophils. C-reactive protein concentration was 186 mg/L, lactate dehydrogenase was 1637 IU/L (normal 285–540), and clotting screen was normal. Ultrasonography showed normal sized unobstructed kidneys with prominent pyramids (fi gure A). There was no serological evidence of systemic lupus erythematosus or systemic vasculitis. Peritoneal dialysis was started. A percutaneous kidney biopsy showed that 90% of the cortex and cortical medulla was necrotic with histological evidence of fi brin in the intra-renal arterioles, consistent with microvascular thrombosis (fi gure B, C). After the biopsy, the haemoglobin concentration fell to 64 g/L, prompting a CT angiogram, which showed no evidence of post-biopsy haemorrhage, patent renal arteries, non-enhancing renal cortex, enhancing medulla, and sparing of a peripheral rim of cortex—appearances characteristic of renal cortical necrosis. Causes for a prothrombotic state leading to cortical thrombosis and subsequent necrosis were sought. Protein S, protein C, and antithrombin III were within the normal ranges; a screen for lupus anticoagulant was positive but no specifi c anti-cardiolipin antibodies were detected (follow-up screen was negative). A test for paroxysmal nocturnal haemoglobinuria was negative. However, haematinic assays showed vitamin B12 defi ciency (72·3 pmol/L) and borderline folate defi ciency (4·53 nmol/L); antibodies to intrinsic factor were not present. Our patient admitted to being a “fussy eater” with a particular aversion to soft food including fruit and vegetables; she lived mostly on biscuits, crisps, and fi zzy drinks. Vitamin supplementation was started. 11 days after admission (8 days after initiation of vitamin supplementation and 5 days after start of peritoneal dialysis), serum homocysteine concentration was high at 76·2 μmol/L (normal <11·1); we concluded that hyperhomocysteinaemia secondary to B12 defi ciency had led to cortical thrombosis and necrosis. Our patient was established on peritoneal dialysis and discharged home 3 weeks after admission. 6 weeks later, serum homocysteine concentration was 3·9 μmol/L; concentrations of organic acids in urine and aminoacids in plasma did not suggest an underlying primary metabolic defect of homocysteine metabolism. She has remained well, but is hypotensive (systolic BP 80–90 mm Hg) despite fl uid overload; an echocardiogram showed poor systolic function. She has been found to have selenium defi ciency and is being investigated for carnitine defi ciency. She was last seen in January, 2010, and was well but still not eating vegetables. Cortical necrosis is a rare cause of kidney failure, thought to arise from occlusion of aff erent arterioles and interlobular arteries in the cortical vasculature. The radiological appearances are unusual, with a hypoechoic circumferential band adjacent to the renal capsule on sonography and a cortical rim sign on CT, both seen on our patient. Causes of cortical necrosis include snake bite, obstetric complications, and prothrombotic states. Hyperhomocysteinaemia as a result of B12 defi ciency has been associated with thrombotic events, including myocardial infarction. Severe hyperhomocysteinaemia, as a result of inherited enzyme defects, renal failure, or vitamin defi ciency, is associated with an increased risk of endothelial activation, and arterial thrombosis. The homocysteine concentrations observed in our patient were much higher than those generally seen in renal failure or in observational studies that have not shown an association between vitamin defi ciency and risk of vascular events.

Risk analysis for deterioration of renal function after pancreas alone transplant.

Chatzizacharias NA, Vaidya A, Sinha S, Sharples E, Smith R, Jones G, Brockmann J, Friend PJ. Risk analysis for deterioration of renal function after pancreas alone transplant. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01534.x. 
© 2011 John Wiley & Sons A/S.