Rakesh Amin

Longitudinal relation between limited joint mobility, height, insulin-like growth factor 1 levels, and risk of developing microalbuminuria: the Oxford Regional Prospective Study

Aims: To determine risk factors for development of microalbuminuria (MA) in relation to detection of limited joint mobility (LJM+) of the interphalangeal joints in a longitudinal cohort of type 1 diabetic (T1DM) subjects. Methods: A total of 479 T1DM subjects diagnosed <16 years were followed from diagnosis of diabetes with annual assessments consisting of assessment of LJM, measurement of HbA1c and insulin-like growth factor 1 (IGF-1), and three urine samples for albumin:creatinine ratio (ACR). Results: After a median follow up of 10.9 years, 162 subjects (35.1%) developed LJM at median age 13.0 years and duration 5.2 years. More subjects developed LJM after compared to before puberty (67.6 v 32.4%). In LJM+ compared to LJM− subjects, HbA1c (mean 10.1 (SD 1.6) v 9.6 (1.4) %)) and ACR levels (median 1.1 (range 0.2–242.9) v 0.9 (0.4–70.7) mg/mmol) were higher, and in a Cox model probability of developing LJM was related to puberty and higher HbA1c levels. ACR levels were higher after detection of LJM compared to before (median 1.2 (range 0.4–102.6) v 0.8 (0.2–181.9) mg/mmol). Probability of developing MA was related to puberty, HbA1c, female sex, and presence of LJM (a 1.9-fold increased risk). Both LJM and MA were associated with lower height SDS (LJM: mean 0.0 (SD 1.0) v 0.2 (1.1); MA: 0.0 (1.0) v 0.2 (SD 1.0)) and lower IGF-1 levels. Conclusion: The development of LJM was associated with an increased risk of microalbuminuria, independent of glycaemic control. Risk for both microalbuminuria and LJM was associated with puberty, reduced growth, and reduced IGF-1 levels, and may indicate underlying shared pathogenic mechanisms.

Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes.

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13–24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1–0.8 mg · kg−1 · day −1) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU · kg−1 · min −1) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (Ra) (P = 0.004), while peripheral glucose uptake (Rd) was not different from placebo. The increase in glucose Rd during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol Ra, a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.

Increasing urine albumin excretion is associated with growth hormone hypersecretion and reduced clearance of insulin in adolescents and young adults with type 1 diabetes: The Oxford Regional Prospective Study

Hypothesisu2002 We previously described lower insulin‐like growth factor I (IGF‐I) levels in association with increased microalbuminuria (MA) risk in type 1 diabetic subjects followed from diabetes diagnosis through puberty into adulthood. By inference lower IGF‐I levels may be associated with higher GH levels and changes in insulin sensitivity.

The effects of a specific growth hormone antagonist on overnight insulin requirements and insulin sensitivity in young adults with Type 1 diabetes mellitus

Aims/hypothesisGrowth hormone hypersecretion in Type 1 diabetes could exacerbate insulin resistance and contribute to declining glycaemic control. Our aim was to determine the effects of specific growth hormone blockade on insulin sensitivity and lipolysis in young adults with Type 1 diabetes.MethodsWe studied the effects of two doses of a specific growth hormone antagonist (B2036-PEG; Somavert, Pharmacia Corporation, Milton Keynes, UK) on insulin sensitivity in seven young adults (17–22 yrs, 3M) with Type 1 diabetes. Subjects recieved 5 and 10 mg B2036-PEG, in random order for 3 weeks, with a 3-week washout. At baseline and following each treatment block, an overnight (03:00 to 08:00xa0h) insulin infusion for euglycaemia (5xa0mmol/l), followed by two-step hyperinsulinaemic euglycaemic clamp, using [6,6 2H2] glucose and 2H5 glycerol to measure glucose and glycerol turnover was performed.ResultsCompared to baseline, overnight insulin requirements decreased with both doses: (means±SEM) 0.34±0.02xa0mU/Kg/min vs 0.25±0.01 (5xa0mg) (p=0.04), and 0.24±0.01 (10xa0mg) (p=0.004). IGF-I (ng/ml) decreased following 10xa0mg [223.5±23.9 vs 154.6±28.1 (p=0.005], but not 5xa0mg. Mean overnight non esterified fatty acid concentrations (mmol/l) decreased with 10xa0mg [0.51±0.04 vs 0.38±0.04 (p=0.03)], as did β-hydroxybutyrate (mmol/l); [0.31±0.04 vs 0.15±0.02 (p=0.004)]. Glycerol production rate, an index of lipolysis, was lower following 10xa0mg (p=0.04), but insulin sensitivity during the clamp did not change with either dose.Conclusion/interpretationTreatment with both doses of B2036-PEG reduced overnight insulin requirements. The 10xa0mg dose suppressed lipolysis and reduced IGF-I. Failure to show enhanced insulin sensitivity during the clamp with the 10xa0mg dose could reflect opposing actions of growth hormone and IGF-I.

Pseudohypoparathyroidism — another monogenic obesity syndrome

Obesity is a common feature of pseudohypoparathyroidism (PHP) type 1a, but is usually associated with short stature. We describe two children referred because of hyperphagia and excessive weight gain from early infancy. Tall stature in both children initially confounded the diagnosis of PHP, but on follow‐up both children developed the typical hormonal abnormalities and Case 2 developed typical skeletal features of Albright hereditary osteodystrophy. u2003PHP type 1a is caused by germline loss of function mutations in the α subunit of GS, the ubiquitously expressed G protein that couples many hormone receptors to the adenylate cyclase second messenger system. Recent evidence suggest that the hypothalamic GS protein coupled melanocortin‐4 receptor (MC4R) may mediate the central effects of leptin on inhibition of satiety. Similar patterns of infancy onset hyperphagia, excessive weight gain and tall stature are seen in subjects with congenital leptin deficiency and in subjects with MC4R mutations. u2003We suggest that the genetic mutations in GSαwhich underlie PHP type 1a may also directly result in severe obesity. This diagnosis should be considered in any child with a history of hyperphagia and early onset morbid obesity.

Symmetric dimethylarginine, an endogenous marker of glomerular filtration rate, and the risk for microalbuminuria in young people with type 1 diabetes

Objectives To perform a cross-sectional comparison of endogenous markers of glomerular filtration rate (GFR) (plasma symmetric dimethylarginine (SDMA) and estimated GFR (eGFR)) with a direct measure of GFR (using the plasma clearance of Inutest (In-GFR)), and a longitudinal evaluation of these markers in relation to the development of microalbuminuria, in young people with type 1 diabetes (T1D). Methods Longitudinal stored blood samples (n=1105) were available from 417 young people from the Oxford Regional Prospective Study (an inception cohort of 527 children followed for a median of 10.3 (interquartile range 7.1–12.3) years), for measurement of SDMA and creatinine. Additional annually collected data on anthropometric parameters, HbA1c, insulin dose and three early morning albumin:creatinine ratios were available. In-GFR was measured in a representative subgroup of 183 subjects. Main outcome measures SDMA and eGFR. Results SDMA and eGFR were significantly and similarly associated with In-GFR (r=−0.38 and r=0.36, p<0.001). Overall SDMA levels were lower in microalbuminuric (n=116) than normoalbuminuric subjects (n=301) (0.385±0.063 vs 0.412±0.059 µmol/l, p<0.001), probably reflecting hyperfiltration. The pattern of change in SDMA levels with age differed between microalbuminuric and normoalbuminuric subjects. Whereas SDMA levels declined in both groups until the age of 16 years, thereafter they tended to rise only in microalbuminuric subjects, probably reflecting a decline in renal function. Conclusions In this longitudinal study of young people with T1D, measurement of SDMA, in contrast to eGFR, proved to be a reliable marker in identifying changes in filtration rates associated with the development of microalbuminuria (MA).

Unchanged incidence of microalbuminuria in children with type 1 diabetes since 1986: a UK based inception cohort

Aims: To prospectively determine the change in prevalence of microalbuminuria in relation to changes in glycaemic control in children diagnosed with type 1 diabetes between 1986 and 1996. Design: Prospective observational study of an inception cohort. Setting: The geographically defined region of Oxfordshire, UK. Patients: 527 children diagnosed with type 1 diabetes under 16 years of age, were divided into three groups based on year of diagnosis of diabetes: group A (1986–1989, nu200a=u200a165), group B (1990–1993, nu200a=u200a179) and group C (1994–1996, nu200a=u200a183). Each group was followed prospectively for 10 years. Main outcome measures: Cumulative prevalence of microalbuminuria. Results: After 4052 patient years of follow-up, in groups C versus B versus A, the cumulative prevalence of microalbuminuria was 31.7% (95% CI 20.9 to 42.5), 24.8% (17.8 to 31.8) and 23.2% (15.4 to 30.0) (log rank pu200a=u200a0.22), and risk for development of microalbuminuria was not associated with year of onset of diabetes (hazard ratio 1.05 (0.99 to 1.12), pu200a=u200a0.11). In groups C versus B versus A, glycaemic control improved after 10 years of diabetes (mean HbA1c 8.9% (1.5%) vs 9.4% (1.5%) vs 10.1% (1.7%), p value for ANOVA <0.001) and more children achieved an HbA1c level <7.5% (15.6% vs 5.9% vs 6.1%, p value for ANOVAu200a=u200a0.032). Conclusion: In this UK based inception cohort of children diagnosed with type 1 diabetes, the adjusted prevalence of microalbuminuria was unchanged since 1986, despite some improvements in glycaemic control. This observation highlights the need for more proactive intervention with drugs such as angiotensin converting enzyme (ACE) inhibitors.

Markers of microvascular complications in insulin dependent diabetes

Annual screening for early markers of microvascular disease during puberty should be encouragednnScreening for early markers of microvascular disease is now generally recommended from around the age of 10 years in children with type 1 diabetes mellitus (TIDM). Annual assessment should include direct fundal examination or fundus photography, monitoring of arterial blood pressure (BP), and measurement of urinary albumin excretion. The basis of all screening programmes is that those most at risk can be correctly identified and that there should be appropriate and effective interventions. The value of retinal screening is beyond doubt as the detection of early preproliferative or proliferative retinopathy may lead to successful intervention with laser therapy, but such events are rare before the age of 18 years. The evidence supporting screening for other markers of microvascular disease, such as microalbuminuria (MA) and hypertension is more contentious and this is the subject of the current review. Symptomatic autonomic or sensory nephropathy is relatively rare in children and adolescents and this will not be discussed further.nnThe decision to introduce screening at age 10 years reflects the influence of puberty on the risk for microvascular disease. Several cross sectional studies and at least two large longitudinal studies (the Berlin Retinopathy Study and the Oxford Regional Prospective Study (ORPS)) have shown that microvascular complications are rare before puberty.1,2 Puberty confers a three- to fourfold increase in risk of MA after adjusting for other major risk factors such as diabetes duration, HbA1c, and gender.1,3 Prepubertal duration of diabetes may contribute to the risk of MA, but this only becomes evident after the onset of puberty.1 Contrary to historical belief, MA is not rare4 and may progress5 within the first five years after the diagnosis of TIDM in pubertal subjects.4,5 Puberty …

Growth hormone hypothesis and development of diabetic nephropathy in Type 1 diabetes

In Type 1 diabetes, poor glycemic control is the key predictor for the development of microalbuminuria, an established early marker of overt nephropathy. However, the role of other pathways in the development of diabetic nephropathy may also be important. The growth hormone (GH) hypothesis suggests that the GH–insulin-like growth factor (IGF)-1 axis may play an important role in this disease process. In Type 1 diabetes, the characteristic pattern of GH hypersecretion and low circulating IGF-1 levels results from hepatic GH resistance owing to the lack of portal insulin. Clinical data indicate that high GH and low IGF-1 levels reduce insulin sensitivity and worsen glycemic control. Furthermore, despite hepatic GH resistance, GH receptors at the kidney remain intact. Experimental data show that excess GH stimulates renal GH receptors and, through paracrine IGF-1 production, results in pathophysiological changes consistent with diabetic nephropathy, namely nephromegaly, glomerular hyperfiltration and eventual proteinuria. These abnormalities are reversed by intervention to block or normalize the local effects of GH and IGF-1. Although such data in humans are limited, preliminary trials show that interventions to increase IGF-1 levels and reduce GH hypersecretion improve glycemic control and insulin sensitivity in the short term. However, their effects on early nephropathy and end points, such as the prevalence of end stage renal disease, have yet to be determined.