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Anthony H Barnett

Publications and source records attributed to Anthony H Barnett.

18 recordsLinked to original sources
PubMed2006

An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with metformin as adjunctive therapy in patients with type 2 diabetes poorly controlled on a sulfonylurea.

OBJECTIVE: To compare the efficacy and safety profile of adding inhaled human insulin (INH; Exubera) or metformin to sulfonylurea monotherapy in patients with poorly controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an open-label, parallel, 24-week, multicenter trial. At week -1, patients uncontrolled on sulfonylurea monotherapy were divided into two HbA(1c) (A1C) arms: > or =8 to < or =9.5% (moderately high) and >9.5 to < or =12% (very high). Patients were randomized to adjunctive premeal INH (n = 225) or metformin (n = 202). The primary efficacy end point was change in A1C from baseline. RESULTS: In the A1C >9.5% arm, INH demonstrated a significantly greater reduction in A1C than metformin. Mean adjusted changes from baseline were -2.17 and -1.79%, respectively; between-treatment difference was -0.38% (95% CI -0.63 to -0.14, P = 0.002). In the A1C < or =9.5% arm, mean adjusted A1C changes were -1.94 and -1.87%, respectively (-0.07% [-0.33 to 0.19], P = 0.610), consistent with the noninferiority criterion. Hypoglycemia (events/subject-month) was greater in the INH (0.33) than in the metformin (0.15) group (risk ratio 2.16 [95% CI 1.67-2.78]), but there were no associated discontinuations. Other adverse events, except increased cough in the INH group, were similar. At week 24, changes in pulmonary function parameters were small and comparable between groups. Insulin antibody binding increased more with INH but did not have any associated clinical manifestations. CONCLUSIONS: In patients with type 2 diabetes poorly controlled on a sulfonylurea (A1C >9.5%), the addition of premeal INH significantly improves glycemic control compared with adjunctive metformin and is well tolerated.

Administration, Inhalation↗
PubMed2006

An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with glibenclamide as adjunctive therapy in patients with type 2 diabetes poorly controlled on metformin.

OBJECTIVE: To compare the efficacy and safety profile of adding inhaled human insulin (INH) (Exubera) or glibenclamide to metformin monotherapy in patients with poorly controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted an open-label, parallel, 24-week multicenter trial. Patients uncontrolled on metformin were randomized to adjunctive INH (n = 243) or glibenclamide (n = 233). Before randomization, patients were divided into two HbA(1c) (A1C) arms: > or =8 to < or =9.5% (moderately high) and >9.5 to < or =12% (very high). The primary efficacy end point was A1C change from baseline. RESULTS: Mean adjusted A1C changes from baseline were -2.03 and -1.88% in the INH and glibenclamide groups, respectively; between-treatment difference -0.17% (95% CI -0.34 to 0.01; P = 0.058), consistent with the noninferiority criterion. In the A1C >9.5% arm, inhaled insulin demonstrated a significantly greater reduction in A1C than glibenclamide, between-treatment difference -0.37% (-0.62 to -0.12; P = 0.004). In the A1C < or =9.5% arm, between-treatment difference was 0.04% (-0.19 to 0.27; P = 0.733). Hypoglycemia (events per subject-month) was greater with INH (0.18) than glibenclamide (0.08), risk ratio 2.24 (1.58-3.16), but there were no associated discontinuations. Other adverse events, except increased cough in the INH group, were similar. At week 24, changes from baseline in pulmonary function parameters were small. Insulin antibody binding increased more with INH but did not have any associated clinical manifestations. CONCLUSIONS: In patients with type 2 diabetes poorly controlled on metformin, adding INH or glibenclamide was similarly effective in improving glycemic control, and both were well tolerated. A predefined subgroup with very high A1C (>9.5%) was more effectively treated with the addition of INH.

Adult↗
PubMed2006

Prevalence of microalbuminuria and hypertension in South Asians and white Europeans with type 2 diabetes: a report from the United Kingdom Asian Diabetes Study (UKADS).

Microalbuminuria is more common in South Asian individuals compared to white Europeans. The aim of this study was to determine the relationship between blood pressure and microalbuminuria in a cohort of patients with type 2 diabetes in these two ethnic groups. These further data were analysed from 552 patients (311 South Asian patients and 241 white Europeans) who had microalbuminuria screening data collected. Prevalence of microalbuminuria was significantly higher in South Asian compared with white European patients (31% versus 20%, p=0.007). Among patients with normal, untreated blood pressure, the proportion who had microalbuminuria was three times higher among South Asian patients compared with the white European group (30.7% versus 10.1%, p=0.049, relative risk = 3.1 [1.0-9.5]). In addition, despite their higher cardiovascular risk, South Asian patients were less likely to be prescribed a statin or antihypertensive drug treatment. In conclusion, thresholds and targets for treatment of cardiovascular risk factors in South Asians may need to be lower than those for white Europeans, and targeted intervention will be required to achieve this.

Adult↗
PubMed2006

Inhaled insulin (Exubera): Combining efficacy and convenience.

The pulmonary route, due to its rich vascularity, large surface area and immunotolerant characteristics, may be an ideal target for drug delivery. Although the inhaled route has been used to deliver drugs used in the management of respiratory disorders, success with peptide delivery has been limited by poor bioavailability. Recent advances in technology have overcome these barriers and have enabled new delivery devices to be developed. Insulin is the first peptide to be delivered successfully by this route and the first of the inhaled insulin delivery devices (Exubera) has now been approved for clinical use. In clinical trials it has been shown to be effective, apparently safe and a preferred alternative to subcutaneously injected meal-time insulin. This new technology offers great convenience to patients needing insulin treatment. While it will considerably reduce the number of injections needed by people with type 1 and type 2 diabetes, it should also encourage more patients to start insulin treatment earlier. The potential benefits from improved adherence and better glycaemic control with this insulin are also significant.

Administration, Inhalation↗
PubMed2005

Exenatide.

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.

Adolescent↗
PubMed2004

Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.

BACKGROUND: Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors in persons with type 2 diabetes. METHODS: In this prospective, multicenter, double-blind, five-year study, we randomly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan (80 mg daily, in 120 subjects) or the ACE inhibitor enalapril (20 mg daily, in 130 subjects). The primary end point was the change in the glomerular filtration rate (determined by measuring the plasma clearance of iohexol) between the baseline value and the last available value during the five-year treatment period. Secondary end points included the annual changes in the glomerular filtration rate, serum creatinine level, urinary albumin excretion, and blood pressure; the rates of end-stage renal disease and cardiovascular events; and the rate of death from all causes. RESULTS: After five years, the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 (where the minus sign denotes a decrement) in the telmisartan-treated subjects, as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects; the treatment difference was thus -2.6 ml per minute per 1.73 m2 (95 percent confidence interval, -7.1 to 2.0 ml per minute per 1.73 m2)[corrected] The lower boundary of the confidence interval, in favor of enalapril, was greater than the predefined margin of -10.0 ml per minute per 1.73 m2, indicating that telmisartan was not inferior to enalapril. The effects of the two agents on the secondary end points were not significantly different after five years. CONCLUSIONS: Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes. These findings do not necessarily apply to persons with more advanced nephropathy, but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events.

Adult↗
PubMed2004

Polymorphisms of interleukin 4 receptor gene and interleukin 10 gene are not associated with Graves' disease in the UK.

Graves' disease (GD) is an autoimmune disorder of the thyroid gland and both environmental and genetic factors contribute to disease aetiology. Cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10), are involved in the immune response and may be implicated in the autoimmune disease process. Associations have been reported between single nucleotide polymorphisms (SNPs) of IL-10 and the Ile50Val polymorphism of the IL-4 receptor gene (IL-4R) gene and atopy and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The autoimmune diseases cluster within families and susceptibility genes may overlap between the different disorders. Therefore, we investigated 5 SNPs (-592C/A, -657G/A, - 819C/T, -1349A/G, and -2013G/A) in the promoter region of the IL-10 and the Ile50Val polymorphism (A/G) in the IL-4R in a large UK population based case-control dataset with GD. No association was found between the polymorphisms studied and GD and no significant differences were found in genotype or allele frequencies between the patients and control subjects. We conclude these polymorphisms of IL-10 and IL-4R previously associated with other immune mediated diseases, do not confer susceptibility to GD in white Caucasians in the United Kingdom.

Genetic Predisposition to Disease↗
PubMed2004

Cost-effective strategies in the prevention of diabetic nephropathy.

A significant subgroup of patients with diabetes mellitus are predisposed to developing diabetic nephropathy and it is in this subgroup that other diabetes- related complications, and in particular greatly increased cardiovascular disease risk, are concentrated. The high personal, social and financial costs of managing end-stage renal failure and the other complications associated with diabetic nephropathy make a powerful case for screening and effective intervention programmes to prevent the condition or retard its progression. As major breakthroughs in finding genetic susceptibility factors remain elusive, screening efforts continue to be based on microalbuminuria testing, despite increasing recognition of its limitations as a positive predictor of nephropathy. Interventions have been extensively studied, but results remain conflicting. Economic evaluations of such screening and intervention programmes are essential for health planners, yet models of the cost/benefit ratio of such interventions often rely on a rather slim evidence base. Where economic models are developed, they are frequently based on those papers that propound the greatest clinical benefits of a given intervention, leading to a possible over-estimation of the advantages of the chosen approach. Furthermore, the benefits of even such generally accepted interventions as ACE inhibitor treatment are less firmly established than generally appreciated. Lifestyle interventions are instinctively attractive, but are by no means a low-cost option (as is often assumed by both medical professionals and politicians). This review critically assesses the evidence for clinical efficacy and economic benefit of microalbuminuria screening and interventions such as intensive glycaemic control, antihypertensive treatment, ACE inhibition and angiotensin receptor blockade, dietary protein restriction and lipid-modifying therapy. The various costs associated with diabetic nephropathy are so great that even expensive interventions may have a favourable cost/benefit ratio, provided they are truly effective.

Albuminuria↗
PubMed2003

A review of basal insulins.

Tight glycaemic control (ideally, HbA1c<7%) is central to reducing the risk of long-term complications of diabetes. This approach, for both Type 1 and Type 2 diabetes, commonly involves the use of basal insulin, and must be achieved with minimal risk of hypoglycaemia (particularly nocturnal episodes). Indeed, concern around hypoglycaemia is a major barrier to achieving tight glycaemic control, and is a common problem with those protracted-acting insulins most frequently used in clinical practice for basal insulin supply. Other drawbacks include inter- and intra-patient variability that compromises dosing reproducibility and unsuitability for single daily dosing. New long-acting human insulin analogues with action profiles designed to overcome these problems are now available in clinical practice or are under evaluation in clinical trials. Clinical evidence suggests efficacy and safety advantages for these analogues over NPH insulin (the most commonly used basal insulin), and may bring closer the goal of tight glycaemic control in patients with diabetes.

Carrier Proteins↗
PubMed2003

Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes.

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

Adipocytes↗
PubMed2002

Analysis of the role of DPB1-encoded amino acids in the genetic predisposition to type I diabetes mellitus.

The role of the DPB1 gene in genetic susceptibility to type I diabetes has yet to be elucidated. Studies of DPB1 alleles are conflicting. Analysis at the amino acid level, rather than consideration of allelic polymorphism, has been informative in determining disease susceptibility encoded by the DRB1 and DQ genes. In this study, therefore, amino acid variation at polymorphic sites of the DPbeta peptide chain encoded by the second exon of the DPB1 gene was analyzed in diabetic and control subjects from white Caucasian, North Indian Asian, and Jamaican populations. Human leukocyte antigen genotypes and haplotypes were analyzed using a logistic-regression approach and the data were conditioned for the effects on disease risk of the DRB1, DQA1, and DQB1 genes. Eight DPbeta amino acid residues were significantly associated with type I diabetes independent of DR and DQ (DPbeta 9, 33, 35, 36, 55, 56, 57, and 69). None of these residues, however, correlated consistently with disease risk in all three racial groups. This contrasts with findings for the DRbeta, DQalpha and DQbeta peptide chains, where the identity of the amino acid at particular sites has been found to correlate with predisposition to type I diabetes.

Alleles↗
PubMed2002

Glucocorticoid regulation of p450 aromatase activity in human adipose tissue: gender and site differences.

The distinct gender-specific patterns of fat distribution in men and women (android and gynoid) suggest a role for sex steroids. In keeping with these observations, it has been suggested that estrogens can promote preadipocyte cell proliferation and/or differentiation. The enzyme aromatase P450 is responsible for the conversion of androgen precursor steroids to estrogens and may, therefore, have a role in regulating adipose tissue mass and its distribution. We have investigated the glucocorticoid regulation of aromatase expression in human adipose tissue, specifically to define any site- and gender-specific differences. Abdominal subcutaneous (Sc) and omental (Om) adipose tissue was obtained from male and female patients undergoing elective surgery. After collagenase digestion, preadipocytes were cultured in serum-free medium, for 6-10 d, until confluent with either cortisol (10(-6) M, 10(-7) M) or insulin (500 nM) or a combination of both treatments. Adipocytes were studied in suspension cultures. Aromatase activity was assessed using tritiated [1 beta-(3)H]-androstenedione as substrate. In Sc preadipocytes, basal aromatase activity increased in females from 11.5 +/- 1.4 (mean plus minus SEM) to 28.0 +/- 1.8 pmol/mg x h (n = 17, P < 0.05) with 10(-6) M cortisol. By contrast, in males, aromatase activity was inhibited by 10(-6) M cortisol (19.4 +/- 2.4 pmol/mg x h vs. 7.5 +/- 1.3, n = 9, P < 0.01; men vs. women, P < 0.005). These data were endorsed through Western blot analysis using an in-house antihuman aromatase antibody, which recognized a specific 55-kDa species. Aromatase activity was less at Om sites in preadipocytes, increasing in females from 1.1 +/- 0.2 to 3.2 +/- 0.7 pmol/mg x h with 10(-6) M cortisol (P < 0.05) and in males from 2.6 +/- 0.1 pmol/mg x h to 7.8 +/- 0.3 pmol/mg x h after cortisol (men vs. women, P < 0.001). Cortisol-induced aromatase activity in Om adipocytes from postmenopausal females was higher than that in premenopausal females (P < 0.001). Insulin had no independent effect on aromatase expression, but coincubation of preadipocytes with cortisol and insulin eliminated both gender- and site-specific differences. In conclusion, in women, but not men, cortisol increased aromatase activity at Sc sites, and this may facilitate predilection for Sc adiposity in females. The observed site-, gender-, and menopausal-specific differences in the glucocorticoid regulation of this enzyme may contribute to the gender- and menopausal-specific patterns of fat distribution.

Adipose Tissue↗
PubMed2002

Increased resistin gene and protein expression in human abdominal adipose tissue.

Resistin, a novel signalling molecule isolated in mice has been suggested to be the putative hormone thought to link obesity with type 2 diabetes. The aim of this study was to examine resistin protein expression in human adipose tissue depots and resistin secretion in isolated adipose cells, to characterize resistin expression in human adipose tissue. Both resistin mRNA and protein expression were analysed from human adipose tissue (n = 5 adipose tissue samples: abdominal subcutaneous (Sc) n = 19, abdominal omental adipose tissue (Om) n = 10, thigh n = 9, breast n = 7). Resistin protein expression levels were similar in both the abdominal Sc and Om adipose tissue depots, and expression in abdominal fat depots were increased compared with thigh (p < 0.001) and breast tissue depots (p < 0.001). These findings were consistent with the mRNA expression studies. Resistin was secreted from both pre-adipocytes and adipocytes cells. Thus, resistin resides within isolated adipose cells and is expressed and secreted in human adipose tissue. In conclusion, this study confirms the expression of resistin in human adipose tissue and increased expression in abdominal fat, this suggests a potential role in linking central obesity to type 2 diabetes and/or cardiovascular disease.

Abdomen↗
PubMed2002

Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro.

Lipolysis is an important process determining fuel metabolism, and insulin regulates this process in adipose tissue. The aim of this study was to investigate the long-term effects of insulin, an insulin enhancer (rosiglitazone [RSG]), and insulin in combination with RSG on the regulation of lipolysis and lipogenesis in human abdominal subcutaneous fat. Lipolysis and lipogenesis were assessed by protein expression studies of hormone-sensitive lipase (HSL) (84 kDa) and lipoprotein lipase (LPL) (56 kDa), respectively. In addition, lipolytic rate was assessed by glycerol release assay and tumor necrosis factor (TNF)-alpha release measured by enzyme-linked immunosorbent assay (n = 12). In subcutaneous adipocytes, increasing insulin doses stimulated LPL expression, with maximal stimulation at 100 nmol/l insulin (control, 1.0 +/- 0.0 [mean +/- SE, protein expression relative to control]; 1 nmol/l insulin, 0.87 +/- 0.13; 100 nmol/l insulin, 1.68 +/- 0.19; P < 0.001). In contrast, insulin at the 100 nmol/l dose reduced the expression of HSL (100 nmol/l insulin, 0.49 +/- 0.05; P < 0.05), while no significant reduction was observed at other doses. Higher doses of insulin stimulated both HSL (1,000 nmol/l insulin, 1.4 +/- 0.07; P < 0.01) and LPL (control 1.00 +/- 0.0; 1,000 nmol/l insulin, 2.66 +/- 0.27; P < 0.01) protein expression. Cotreatment with RSG induced an increased dose response to insulin for LPL and HSL (P < 0.05); RSG alone also increased LPL and HSL expression (P < 0.05). Insulin stimulated TNF-alpha secretion in a dose-dependent manner (P < 0.01); the addition of RSG (10(-8) mol/l) reduced TNF-alpha secretion (P < 0.05). In summary, chronic treatment of human adipocytes with insulin stimulates lipolysis and LPL protein expression. The addition of RSG reduced the lipolytic rate and TNF-alpha secretion. The increase in lipolysis is not explained by changes in HSL expression. These data, therefore, may explain in part why hyperinsulinemia coexists with increased circulating nonesterified free fatty acids and increased adiposity in obese and/or type 2 diabetic patients.

Adipocytes↗
PubMedDate not supplied

Cross-cultural comparisons of anxiety and depression in adults with type 1 diabetes.

BACKGROUND: Symptoms of depression and anxiety may be more prevalent in individuals with diabetes; however, little is known about possible differences with respect to social or cultural environment. The aim of this study was to examine cross-cultural differences in prevalence and correlates of symptoms of anxiety and depression in two studies, one in the United Kingdom and one in the United States. METHODS: Adults with type 1 diabetes participating in two studies in Birmingham, UK, and Pittsburgh, US, completed psychosocial questionnaires including the Beck Depression Inventory and the Beck Anxiety Scale. RESULTS: UK subjects were significantly more likely to report moderate-severe levels of anxiety compared to US subjects (17% vs 5%; p < 0.001). Similar proportions of UK and US subjects reported moderate-severe levels of depressive symptomatology (9% vs 7%). Gender differences in symptomatology were more apparent in the US sample than in the UK study population. Multiple regression analysis demonstrated that for the UK study, symptoms of depression, less physical activity and greater frequency of blood glucose monitoring were significantly associated with symptoms of anxiety. Symptoms of depression were also significantly associated with anxiety in the US sample. For UK subjects, depressive symptoms were significantly associated with higher anxiety scores, whereas in the US subjects, anxiety and smoking were significant independent correlates of depression. CONCLUSIONS: These data suggest that there may be cultural and/or gender differences in the experience of symptoms of anxiety and depression, and also differences in the relationship between psychological symptomatology and diabetes self-care. Our findings have implications for the understanding of the role psychosocial factors play in the management of diabetes.

Adult↗
PubMedDate not supplied

The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes.

The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0.003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect.

Adolescent↗