A national survey of the current state of screening services for diabetic retinopathy: ABCD-diabetes UK survey of specialist diabetes services 2006.

The main aims were to ascertain the progress made in the implementation of retinal screening services and to explore any barriers or difficulties faced by the programmes. The survey focused on all the essential elements for retinal screening, including assessment and treatment of screen-positive cases. Eighty-five per cent of screening programmes have a coordinated screening service and 73% of these felt that they have made significant progress. Eighty-five per cent of screening units use 'call and recall' for appointments and 73.5% of programmes follow the National Screening Committee (NSC) guidance. Although many units worked closely with ophthalmology, further assessment and management of screen-positive patients was a cause for concern. The fast-track referral system, to ensure timely and appropriate care, has been difficult to engineer by several programmes. This is demonstrated by 48% of programmes having waiting lists for patients identified as needing further assessment and treatment for retinopathy. Ophthalmology service for people with diabetic retinopathy was provided by a dedicated ophthalmologist in 89.4% of the programmes. Sixty-six per cent of the programmes reported inadequate resources to sustain a high-quality service, while 26% highlighted the lack of infrastructure and 49% lacked information technology (IT) support. In conclusion, progress has been made towards establishing a national screening programme for diabetic retinopathy by individual screening units, with a number of programmes providing a structured retinal screening service. However, programmes face difficulties with resource allocation and compliance with Quality Assurance (QA) standards, especially those which apply to ophthalmology and IT support. Screening programmes need to be resourced adequately to ensure comprehensive coverage and compliance with QA.

Angiotensin-1-converting enzyme (ACE) gene polymorphism, plasma ACE levels, and their association with the metabolic syndrome and electrocardiographic coronary artery disease in Pima Indians.

In Caucasian subjects, an insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with coronary artery disease (CAD) and fatal myocardial infarction. The underlying mechanism(s) of this association is not fully understood. Pima Indians have a low incidence of nonfatal and fatal CAD despite a high prevalence of diabetes. In Pima Indians, circulating ACE levels are related to ACE genotype, but the frequency of the D allele is significantly lower than in Caucasians. A lower frequency of the D allele may underlie a low risk of CAD in this population. We examined the relationship of the ACE genotype and plasma ACE level with electrocardiographic evidence of CAD (Tecumseh criteria), hypertension, and metabolic variables associated with insulin resistance in 305 (146 men and 159 women aged 47+/-9.0 years) Pima Indians characterized for the ACE I/D genotype. The distribution of ACE genotypes was unrelated to diabetes and obesity. Fasting plasma insulin, plasminogen activator inhibitor-1 (PAI-1) activity, plasma triglyceride concentrations, and systolic (SBP) and diastolic (DBP) blood pressure were not significantly different between the three ACE genotypes among nondiabetic and diabetic subjects. There was no significant association of ACE genotype with electrocardiographic evidence of CAD or with hypertension. Plasma ACE concentrations were not significantly different between nondiabetic and diabetic subjects (median, 77 [range, 21 to 1691 v 83 [7 to 238] IU/mL, P=NS). In all subjects, plasma ACE levels were associated weakly with plasma triglyceride (partial r=.20, P < .01) and total cholesterol (partial r=.13, P <.03) concentrations, but not with fasting plasma insulin or PAI-1 activity. In diabetic subjects, ACE levels were related to fasting plasma glucose concentrations (partial r=.15, P=.07). These findings would suggest that ACE gene I/D polymorphism is unlikely to be a major determinant of susceptibility to CAD in Pima Indians. Plasma ACE levels, but not ACE genotype, correlated with lipids, plasma glucose, and blood pressure, suggesting that elevated plasma ACE levels may contribute to the link between insulin resistance and CAD disease or may be a consequence of it.

Intact proinsulin, des 31,32 proinsulin, and specific insulin concentrations among nondiabetic and diabetic subjects in populations at varying risk of type 2 diabetes.

OBJECTIVE: To examine hyperinsulinemia, insulin secretion, and beta-cell function in Pima Indians, South Asians, and whites, populations at varying risk of diabetes. RESEARCH DESIGN AND METHODS: We investigated 136 Pima Indian, 98 Asian, and 80 white nondiabetic and 172 Pima Indian, 40 Asian, and 49 white diabetic subjects. Highly specific assays for insulin, intact proinsulin, and des 31,32 proinsulin were used. Insulin secretion was assessed using ratio of increment (0 to 30 min) in insulin to glucose concentrations during an oral glucose tolerance test (OGTT). RESULTS: Nondiabetic Pima Indians were significantly more obese than Asians and whites. Pima Indian subjects had significantly higher (P < 0.01) fasting insulin concentrations (median 109 pmol/l, range 40-250) than Asian (37 pmol/l, range 17-91) and white (30 pmol/l, range 10-82) subjects. These differences remained significant when controlled for obesity. Nondiabetic Pima Indians also had higher fasting C-peptide concentrations and higher early insulin secretion during an OGTT. Fasting concentrations of intact proinsulin and des 31,32 proinsulin were also significantly higher in Pima Indians (P < 0.01). However, the proportion of proinsulin-like molecules was significantly lower (P < 0.01) in Pima Indians (median 7.9% vs. 12.7% for South Asians and 12.2% for whites). Subjects with diabetes from the three ethnic groups showed significantly higher fasting insulin concentrations but lower 30-min insulin and lower ratios of increment (0-30 min) in insulin to glucose concentrations than did nondiabetic subjects. The proportion of proinsulin-like molecules was not significantly different in diabetic subjects from the three ethnic groups. CONCLUSIONS: These specific assays for insulin indicate that after adjusting for obesity nondiabetic Pima Indians are truly hyperinsulinemic, which is consistent with their insulin resistance as measured by other methods. Hyperinsulinemia in this population with a high risk of diabetes is likely to be due to enhanced insulin secretion. Furthermore, in Pima Indians, the predominant beta-cell secretory product is insulin and not its precursors. We conclude that the differences in the risk of diabetes among these three groups are not due to differences in insulin secretion or insulin processing. Subjects with type 2 diabetes have defective early insulin secretion during OGTTs but show fasting hyperinsulinemia even when specific assays for insulin are used.

Randomized clinical trial of lifestyle interventions in Pima Indians: a pilot study.

A pilot trial was conducted to test adherence to specific lifestyle interventions among Pima Indians of Arizona, and to compare them for changes in risk factors for diabetes mellitus. Ninety-five obese, normoglycaemic men and women, aged 25-54 years, were randomized to treatments named 'Pima Action' (Action) and 'Pima Pride' (Pride), which were tested for 12 months. Action involved structured activity and nutrition interventions, and Pride included unstructured activities emphasizing Pima history and culture. Adherence to interventions, changes in self-reported activity and diet, and changes in weight, glucose concentrations, and other risk factors were assessed regularly. Thirty-five eligible subjects who had declined randomization were also followed as an 'observational' group and 22 members of this group were examined once at a median of 25 months for changes in weight and glucose concentration. After 12 months of intervention, members of both intervention groups reported increased levels of physical activity (median: Action 7.3 h month(-1), Pride 6.3 h month(-1), p < 0.001 for each), and Pride members reported decreased starch intake (28 g, p = 0.008). Body mass index, systolic and diastolic blood pressures, weight, 2-h glucose and 2-h insulin had all increased in Action members (p < 0.003 for each), and waist circumference had decreased in Pride members (p = 0.05). Action members gained more weight than Pride members (2.5 kg vs 0.8 kg, p = 0.06), and had a greater increase in 2-h glucose than Pride members (1.33 mM vs 0.03 mM, p = 0.007). Members of the observational group gained an average of 1.9 kg year(-1) in weight and had an increase of 0.36 mM year(-1) in 2-h glucose. Sustaining adherence in behavioural interventions over a long term was challenging. Pimas may find a less direct, less structured, and more participative intervention more acceptable than a direct and highly structured approach.

Diabetic retinopathy, promoter (4G/5G) polymorphism of PAI-1 gene, and PAI-1 activity in Pima Indians with type 2 diabetes.

OBJECTIVE: To examine the relationship between plasma plasminogen activator inhibitor 1 (PAI-1) activity and PAI-1 gene (4G/5G) polymorphism and diabetic retinopathy in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 171 Pima Indians with type 2 diabetes between the ages of 30-70 years in a population-based epidemiological survey. Plasma PAI-1 activity was measured by a spectrophotometric assay and PAI-1 4G/5G promoter genotype by the polymerase chain reaction (PCR) using allele-specific primers. Retinopathy was assessed by ophthalmoscopy after pupillary dilation and classified as any retinopathy or as nonproliferative and proliferative. RESULTS: Retinopathy was present in 70 (41%) subjects, and 4 (2.3%) subjects had proliferative retinopathy. Plasma PAI-1 activity was not significantly different among subjects with and without retinopathy (17.1 +/- vs. 19.7 +/- 9.1 arbitrary units (AU)/ml, P = 0.09). PAI-1 activity was negatively correlated with duration of diabetes (rs = -0.18, P = 0.02). In a logistic regression analysis controlled for age, sex, BMI, and duration of diabetes, any retinopathy was significantly associated with fasting plasma glucose concentrations (P < 0.05), 2-h postload glucose (P = 0.02), and HbA1c (P = 0.008), but not with PAI-1 activity (P = 0.48). The prevalence of retinopathy in the three genotype groups differed significantly (4G/4G, 4G/5G, and 5G/5G were 44, 49, and 24%, respectively; chi 2 = 8.22, df = 2, P = 0.016) and remained significant after controlling for age, sex, BMI, duration of diabetes, glycated hemoglobin, and urine albumin-to-creatine ratio in a logistic regression analysis. The odds ratios for retinopathy in subjects with 4G/4G and 4G/5G, compared with the 5G/5G genotype, were 2.0 and 3.1, respectively. CONCLUSIONS: Although diabetic retinopathy in Pima Indians with type 2 diabetes is not associated with PAI-1 activity, subjects with the 4G/4G and 4G/5G genotype had a higher prevalence of retinopathy compared with 5G/5G PAI-1genotype. These preliminary findings indicate that in Pima Indians with type 2 diabetes, presence of the 4G allele of the PAI-1 gene was associated with a higher risk of diabetic retinopathy.

The relationship of concentrations of insulin and proinsulin-like molecules with coronary heart disease prevalence and incidence. A study of two ethnic groups.

OBJECTIVE: To define the potential role of proinsulin-like molecules as risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: Fasting concentrations of proinsulin, des-31,32-proinsulin, and insulin, and of insulin 2 h after a 75-g glucose load, were measured in 1,034 nondiabetic europid subjects and 257 south Asian subjects and related to prevalent coronary heart disease (Minnesota-coded electrocardiographic criteria or ischemic chest pain). In 137 south Asian subjects, the fasting concentrations were related to incident coronary heart disease over a 6.5-year follow-up. RESULTS: The standardized odds ratios for prevalent coronary heart disease were as follows: fasting insulin, 1.29 (1.11-1.49), P = 0.0006; 2-h insulin, 1.25 (1.08-1.45), P = 0.003; proinsulin, 1.23 (0.99-1.53), P = 0.058; and des-31,32-proinsulin, 1.32 (1.03-1.69), P = 0.026. The odds ratios were similar in the two ethnic groups. These relationships became insignificant when controlling for age, sex, and BMI. The standardized odds ratios for incident coronary heart disease were as follows: fasting insulin, 0.99 (0.63-1.55), P = 0.97; proinsulin, 1.13 (0.72-1.78), P = 0.59; and des-31,32-proinsulin, 1.00 (0.61-1.63), P = 1.00. CONCLUSIONS: We have found similar relationships between concentrations of proinsulin-like molecules and prevalent coronary heart disease, as are observed for insulin in these nondiabetic subjects, although these molecules comprise only approximately 10% of all insulin-like molecules. It appears biologically implausible that these relationships represent cause and effect.

Diabetic retinopathy assessed by fundus photography in Pima Indians with impaired glucose tolerance and NIDDM.

In a population-based epidemiological study, 991 Pima Indians with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 288 without diabetes aged > or =15 years were examined for retinopathy by fundus photography with a 45 degrees fundus camera after mydriasis. The photographs were graded using a modified Airlie-House classification scheme. The associations of several factors with retinopathy were studied by logistic regression. Non-proliferative retinopathy was present in 11.2 % (19/169) subjects at the time of diagnosis of diabetes and in 8.3% (4/48) in newly diagnosed subjects who had a documented non-diabetic oral glucose tolerance test within 4 years prior to diagnosis of diabetes. The prevalence of retinopathy in subjects with impaired glucose tolerance was 12% (8/68). Retinopathy at the time of diagnosis of diabetes was significantly associated with lower body mass index and higher systolic blood pressure but not glycaemia. Retinopathy was present in 375 (37.8 %) diabetic subjects and 14 (5.2 %) non-diabetic subjects. Among all subjects with diabetes (duration 0-37 years), stepwise multivariate analysis showed non-proliferative retinopathy to be associated with duration of diabetes, mean blood pressure, fasting plasma glucose, treatment with insulin and albuminuria. Proliferative retinopathy was seen in 34 (2.7%) of diabetic and none of the non-diabetic subjects, and was associated with 2 h post-load glucose concentrations, as well as albuminuria, insulin treatment, younger age, and diastolic blood pressure. These data confirm the need for fundus examination at the time of diagnosis of diabetes and during long-term follow-up. Albuminuria and blood pressure are potentially modifiable risk factors and the impact of treating these on incidence and progression of diabetic retinopathy need to be assessed.

Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome.

Elevated plasminogen activator inhibitor-1 may contribute to vascular disease in diabetes mellitus. Pima Indians have a low incidence of cardiovascular disease despite having a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) which in this population is not associated with elevated plasminogen activator inhibitor-1 activity. In Caucasians an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene that has been related to activity levels of its protein in plasma differentially binds repressor and enhancer elements. In 265 Pima Indians (133 diabetic, 132 non-diabetic, 129 male, 136 female, male, mean age 46.6, range 34-68 years) the promoter genotype frequencies were 23.0% for 4G/4G, 49.8% for 4G/5G and 27.2% for 5G/5G compared to 35.4%, 50.8% and 13.8% respectively, (chi 2 = 15.3, 2 df, p < 0.0005) previously reported in Caucasians with NIDDM. The mean plasma activity levels in the three genotypes in the Pima Indians were 18.2, 19.1 and 18.1 U/ml, respectively. Plasminogen activator inhibitor-1 activities correlated with plasma insulin (r = 0.38, p < 0.0001), body mass index (r = 0.24, p < 0.0001), and with triglyceride level (r = 0.12, p = 0.054) but there was no relationship between promotor genotype and activity. A steeper regression slope between plasminogen activator inhibitor-1 activity and triglycerides has been observed in Caucasians with the 4G/4G genotype as compared to Caucasians with the other genotypes. This was not found in the Pima population which may indicate a functional difference in this gene associated with reduced cardiovascular risk and may be involved in the lack of association of plasminogen activator inhibitor-1 levels with NIDDM in Pima Indians.

Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians.

Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resistance and several components of the insulin resistance syndrome, and PAI-1 levels are elevated in subjects with non-insulin-dependent diabetes mellitus. Many Pima Indians are obese, insulin-resistant, and hyperinsulinemic, and they have high rates of diabetes but a low risk of ischemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To investigate if insulin per se has any effect on PAI-1 in vivo, we also assessed the effects of endogenous (during a 75-g oral glucose load) and exogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twenty-one (14 men and seven women; mean age, 26.3 +/- 4.8 years) Pima Indians underwent a 75-g oral glucose tolerance test (OGTT) and a sequential hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estimated metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsulinemia. PAI-1 antigen was determined using a two-site enzyme-linked immunosorbent assay that detects only free PAI-1. PAI-1 antigen concentrations were significantly related to body mass index ([BMI] rs = .54, P = .012), waist (rs=.52, P=.016) and thigh (rs=.63, P=.002) circumference, and fasting plasma insulin concentration (rs=.59, P=.004). PAI-1 antigen concentrations were not significantly associated with peripheral glucose uptake (M value) during either low-dose (rs= -.01, P=NS) or high-dose (rs= -.11, P=NS) insulin infusion. PAI-1 antigen was negatively correlated with basal hepatic glucose output (rs= -.57, P=.013) and percent suppression of hepatic glucose output during hyperinsulinemia (rs= -.69, P=.005). However, this relationship was largely due to the confounding effects of BMI, waist and thigh girth, fasting insulin, and 2-hour postload glucose concentrations, and was not significant when controlled for these variables (partial rs= -.30, P=NS). There was no significant relationship of PAI-1 antigen concentration with glucose storage or glucose oxidation. Despite a threefold increase in plasma insulin concentrations during the OGTT, there were no significant changes in PAI-1 antigen concentrations (median, 57, 61, 55, and 44 ng/mL at 0, 60, 120, and 180 minutes, respectively; P=NS by ANOVA). During the hyperinsulinemic clamp, mean plasma insulin concentrations at the end of low-dose (240 pmol/m2/min) and high-dose (2,400 pmol/m2/min) infusions were 1,005 and 14,230 pmol/L, respectively. However, PAI-1 antigen concentrations at the end of low-dose and high-dose insulin infusions were similar to those at baseline (median, 63, 43, and 58 ng/mL, respectively; P=NS by ANOVA). PAI-1 antigen in Pima Indians is related to several components of the insulin resistance syndrome. However, direct measurement of insulin resistance indicates that hepatic but not peripheral insulin resistance is related to PAI-1 antigen. Neither endogenous nor exogenous hyperinsulinemia for short periods had any significant effect on PAI-1 antigen concentrations. Short-term hyperinsulinemia is unlikely to be an important regulator of PAI-1 in Pima Indians. The relationship of PAI-1 antigen to hepatic insulin resistance is largely dependent on the relationship of PAI-1 to indices of obesity and fasting insulin concentrations.

Effect of metformin on intact proinsulin and des 31,32 proinsulin concentrations in subjects with non-insulin-dependent (type 2) diabetes mellitus.

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 +/- 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 +/- 2.5 vs placebo: 12.0 +/- 2.3 mmol l-1, p r2 0.001;). Concentrations of intact (median change -2.9 (range -28.4 to +2.5 pmol l-1), p = 0.02) and des 31,32 proinsulin (median change -1.6 (range -14.1 to +5.4 pmol l-1), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change -6% (range -16% to +6%), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r1 = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.

Plasminogen activator inhibitor (PAI-1) and non-insulin-dependent diabetes in Pima Indians, south Asians and Europeans. Populations at varying risk of NIDDM and coronary artery disease.

Activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of fibrinolysis, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to excess macrovascular disease. We investigated the association of PAI-1 activity with NIDDM in Pima Indians, a racial group with low risk of coronary artery disease, but in whom the impact of NIDDM on the occurrence of coronary artery disease is similar to other racial groups. We studied 308 (136 non-diabetic, 172 diabetic) Pima Indians from Arizona, and 138 (98 non-diabetic, 40 diabetic) South Asians and 129 (80 non-diabetic, 49 diabetic) Europeans living in North London. PAI-1 activity was measured by a spectrophotometric assay, and insulin, intact proinsulin and des 31,32 proinsulin concentrations were measured employing highly specific monoclonal antibody-based assays. Compared with non-diabetic subjects, PAI-1 activity was significantly higher in subjects with NIDDM among South Asians (22.8 +/- 7.3 vs. 17.4 +/- 6.9 AU/ml, p < 0.001) and Europeans (23.1 +/- 6.6 vs. 16.5 +/- 6.1 AU/ml, p < 0.001) but not among Pima Indians (19.5 +/- 9.6 vs. 18.5 +/- 8.6 AU/ml, ns). The association of PAI-1 activity with diabetes remained statistically significant when controlled for age, sex, body mass index and waist-hip ratio, serum triglyceride and fasting insulin concentrations in South Asians (p < 0.001) and Europeans (p < 0.001). The relationships of PAI-1 activity with clinical and biochemical variables were similar in the three racial groups other than for fasting and 2 h plasma glucose concentrations which were significantly associated with PAI-1 activity in South Asians (partial r = 0.32 and 0.31) and Europeans (partial r = 0.44 and 0.50) but not in Pima Indians (partial r = 0.11 and 0.15). In Pima Indians with NIDDM, PAI-1 activity was similar in those treated with sulphonylureas, insulin, or no drugs for diabetes. In conclusion, the association of PAI-1 with diabetes differs in racial groups who are at different risk of NIDDM and ischaemic heart disease. Previously reported differences in the prevalence of ischaemic heart disease between diabetic and non-diabetic Pima Indians, and between non-diabetic subjects from the three racial groups, are unlikely to be due to differences in PAI-1 activity.

Low prevalences of chronic widespread pain and shoulder disorders among the Pima Indians.

OBJECTIVE: To establish the prevalence of shoulder disease and chronic widespread pain in Pima Indians. METHODS: Cross sectional analyses of data from 4230 subjects for shoulder disease and 105 subjects for chronic widespread pain participating in population surveys RESULTS: The prevalence of shoulder disease was 4.4% (95% CI, 3.8-5.1), age-sex adjusted to the 1980 US census population. This is lower than in a study of Caucasians [prevalence ratio (PR) = 0.29, 95% CI, 0.20-0.42 for men and PR = 0.55, 95% CI, 0.41-0.73 for women]. Shoulder disease was associated with non-insulin-dependent diabetes mellitus (PR = 1.67, 95% CI, 1.19-2.36). No chronic widespread pain was identified (95% CI, 0-3.5%). CONCLUSION: Prevalence of these pain syndromes in Pima Indians is lower than in predominantly Caucasian populations. These findings suggest that these populations have different pain perception or different patterns of risk factors for these disorders.

Plasminogen activator inhibitor (PAI-1) activity is elevated in Asian and Caucasian subjects with non-insulin-dependent (type 2) diabetes but not in those with impaired glucose tolerance (IGT) or non-diabetic Asians.

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l-1 vs IGT 41 pmol l-1, p < 0.01 and vs normals 34 pmol l-1, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 +/- 6.9 vs IGT 16.8 +/- 5.0, p < 0.001 and vs normals 17.1 +/- 6.9 AU ml-1, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 +/- 7.3 vs 16.5 +/- 6.4 AU ml-1, p = ns) and diabetic (22.8 +/- 7.3 vs 23.1 +/- 6.6 AU ml-1, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist-hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.

Hyperinsulinemia in nondiabetic Asian subjects using specific assays for insulin, intact proinsulin, and des-31, 32-proinsulin.

OBJECTIVE: To investigate the contributions of intact proinsulin and of des-31,32-proinsulin to fasting concentrations of insulin-like molecules in nondiabetic subjects from two ethnic groups (Asian and white) and to see whether Asian subjects are hyperinsulinemic compared with white subjects using highly specific assays for insulin. RESEARCH DESIGN AND METHODS: We investigated subjects with normal glucose tolerance (NGT) (82 Asian and 67 white) and impaired glucose tolerance (IGT) (16 Asian and 13 white), diagnosed by using standard World Health Organization criteria. Highly specific monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des-31,32-proinsulin. An index of insulin secretion was derived as a ratio of incremental insulin to incremental glucose concentrations from 0 to 30 min during an oral glucose tolerance test. RESULTS: Asian subjects with NGT, despite being significantly thinner than whites (BMI 24.4 +/- 3.5 vs. 25.7 +/- 3.7 kg/m2, P = 0.04), had a more central distribution of obesity (subscapsular-to-triceps skinfold ratios 1.36 +/- 0.69 vs. 1.17 +/- 0.41, P = 0.047). Asian subjects with NGT showed significant hyperinsulinemia 2 h after oral glucose load (plasma insulin median 274 pmol/l [range 26-1,505] vs. 186 pmol/l [27-720], P < 0.005) compared with whites. Asian subjects with NGT also had significantly higher insulin increments (P < 0.02) compared with white subjects and significantly higher fasting concentrations of intact proinsulin (median 2.7 pmol/l [range 0.9-14.1] vs. 2.1 [0.8-7.9], P < 0.02) but not of des-31,32-proinsulin. The ratio of proinsulin-like molecules to the total sum of three insulin-like molecules, however, was similar between Asian and white subjects with NGT and IGT. CONCLUSIONS: These results indicate that when specific assays for insulin are used, Asian subjects show postglucose load hyperinsulinemia and fasting hyperproinsulinemia compared with white subjects, suggesting increased insulin secretion and/or the presence of underlying insulin resistance in this ethnic group. The contribution of proinsulin-like molecules to total insulin-like molecules was similar between Asian and white subjects with NGT and IGT, and there was no contribution to hyperinsulinemia in Asian subjects.

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM.

Angiotensin 1 converting enzyme (ACE) catalyses the step which generates angiotensin II, and also inactivates bradykinin, peptides which play a key role in modulating vascular tone. Plasma ACE levels are under genetic control and up to 50% of the variation is due to an insertion/deletion (I/D) polymorphism of ACE gene with highest levels found in DD homozygotes. Studies have shown an association of diabetic nephropathy and ischaemic heart disease with angiotensin converting enzyme gene polymorphism in subjects with diabetes. We examined the association between diabetic retinopathy and ACE gene insertion/deletion polymorphism in 363 subjects with NIDDM (aged 68.3 +/- 10.7 years; 201 male, 162 female), 186 subjects with IDDM (aged 42.4 +/- 15.0 years; 100 male, 86 female) and 98 controls. These subjects were characterized for ACE I/D polymorphism employing standard primers. Diabetic retinopathy was diagnosed by ophthalmoscopy through dilated pupils by an ophthalmologist and classified as non-proliferative or proliferative retinopathy. As expected, diabetic retinopathy was strongly associated with duration of diabetes (p < 0.001) in both IDDM and NIDDM. Any retinopathy was present in 51% subjects with IDDM and 49% of subjects with NIDDM, while 22% of IDDM subjects and 5% of subjects with NIDDM had proliferative retinopathy. The frequency of I allele was 0.477 vs 0.482 vs 0.510 and D allele was 0.523 vs 0.518 vs 0.490, among subjects with IDDM, NIDDM and controls, respectively. The frequency of ACE I/D genotype was similar in subjects with IDDM, NIDDM, and controls (chi 2 = 0.46, df = 4, p = ns). Presence or absence of retinopathy was not significantly associated with ACE genotype in subjects with IDDM (chi 2 = 3.42, df = 2, p = ns) or NIDDM (chi 2 = 0.51, df = 2, p = ns). Among subjects with retinopathy, there was no significant association between ACE genotype and type of retinopathy. Controlled for duration of diabetes, the frequency of I/D genotype was not significantly different in 271 subjects with retinopathy (IDDM and NIDDM combined) when compared with 86 subjects without retinopathy at 15 years or more after diagnosis of diabetes (chi 2 = 1.29, df = 2, p = ns). These findings indicate that I/D polymorphism of ACE gene is not a useful marker and is unlikely to play a major role in determining genetic susceptibility to diabetic retinopathy or the severity of diabetic retinopathy.

Early and late insulin response as predictors of NIDDM in Pima Indians with impaired glucose tolerance.

Risk factors predicting deterioration to diabetes mellitus were examined in 181 subjects with impaired glucose tolerance. Fifty-seven subjects had impaired glucose tolerance on one occasion followed by normal glucose tolerance at a repeat oral glucose tolerance test, and 124 subjects had impaired glucose tolerance on two successive oral glucose tolerance tests. Subjects were followed for a median period of 5.0 years (range 1.0-17.2). The age- and sex-adjusted cumulative incidence of diabetes at 10 years of follow-up was higher in subjects who had impaired glucose tolerance on both tests (70%) than in those whose glucose tolerance was normal at the repeat test (53%), [rate ratio (RR) = 1.6, 95% confidence intervals (CI) = 1.0-2.5]. Proportional hazards analyses were used to identify baseline risk factors (measured at the repeat oral glucose tolerance test) for subsequent diabetes, and incidence rate ratios were calculated for the 90th percentile compared with the 10th percentile of each continuous variable for the whole group. In all subjects, in separate models, higher body mass index [RR = 2.0, 95% CI = 2.2-9.9], high fasting serum insulin concentrations [RR = 2.4, 95% CI = 1.4-4.2], and low early insulin response [RR = 0.5, 95% CI = 0.3-0.8] 30 min after a glucose load were significant predictors for deterioration to diabetes. In a multivariate analysis which controlled for age and sex, 120-min post-load glucose, fasting insulin and late insulin response predicted diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Gynaecomastia caused by a primary mediastinal seminoma.

The case of a young man aged 26 is reported. He presented with a short history of painful gynaecomastia, and no other associated symptoms. Radiological investigations showed a mass in the anterior mediastinum. Endocrine investigations showed high circulating oestradiol and high hCG-beta levels. There was no evidence of primary testicular tumour or metastases. Surgical removal of the mediastinal mass led to normalization of oestradiol and hCG-beta levels and regression of gynaecomastia. Histology showed the tumour to be a primary mediastinal seminoma staining positively for hCG-beta. Further treatment consisted of chemotherapy with etoposide and cis-platinum. The patient has remained well with no evidence of disease recurrence. The tumour markers remain normal.

Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups.

OBJECTIVE: To investigate the effects of metformin on glycemic control, insulin resistance, and risk factors for cardiovascular disease in NIDDM subjects from two ethnic groups (Caucasian and Asian) with different risks of cardiovascular disease. RESEARCH DESIGN AND METHODS: A total of 27 subjects with NIDDM (17 Caucasian, 10 Asian) were given metformin and placebo each for a 12-wk period in a randomized, double-blind, placebo-controlled crossover study, and the dose was increased after 1 and 6 wk, up to a maximum of 850 mg three times a day. Insulin resistance, glycemic control, and cardiovascular risk factors were assessed before and after each treatment phase. The end of 12 wk of metformin treatment was compared with the end of 12 wk of placebo treatment. RESULTS: Metformin treatment was associated with significant improvement in FPG at 6 and 12 wk (mean difference at 12 wk, -3.08 mM, 95% CI -4.12 to -2.04 mM, P < 0.0001) and MCR of glucose (median difference 0.40 ml.kg-1.min-1, interquartile range -0.10 to 1.30 ml.kg-1.min-1, P = 0.036). beta-cell function calculated by HOMA also improved significantly (median difference 14%, interquartile range 7 to 23%, P < 0.001). Total triglyceride (median difference -0.2 mM, interquartile range -0.6 to 0.1 mM, P = 0.034), total cholesterol (mean difference -0.52 mM, 95% CI -0.83 to -0.22 mM, P = 0.002), and LDL cholesterol (mean difference -0.40 mM, 95% CI -0.64 to -0.16 mM, P = 0.002) fell significantly on metformin treatment, whereas no significant changes were observed in HDL cholesterol. PAI-1 activity fell significantly (mean difference -5.3 AU/ml, 95% CI -8.2 to -2.4 AU/ml, P = 0.001), but plasma fibrinogen concentrations and platelet function, spontaneous or agonist induced, were unaffected. UAE was lower on metformin treatment (median difference -2.4 micrograms/min, interquartile range -4.4 to -0.2 micrograms/min, P = 0.004), but metformin had no significant effect on BP. The effects of metformin on glycemic control and cardiovascular risk factors were generally similar in the two ethnic groups. CONCLUSIONS: These findings indicate that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.