John S. Yudkin

Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study

Abstract Objective: To investigate the relation between decreased maternal food intake and risk factors for coronary heart disease in adult Design: Cross sectional study. Subjects: 169 subjects exposed to malnutrition in utero (intrauterine group) during the siege of Leningrad (now St Petersburg) in 1941-4; 192 subjects born in Leningrad just before rationing began, before the siege (infant group); and 188 subjects born concurrently with the first two groups but outside the area of the siege (unexposed group). Setting: Ott Institute of Obstetrics and Gynaecology, St Petersburg. Main outcome measures: Development of risk factors for coronary heart disease and diabetes mellitus—obesity, blood pressure, glucose tolerance, insulin concentrations, lipids, albumin excretion rate, and clotting factors. Results: There was no difference between the subjects exposed to starvation in utero and those starved during infant life in: (a) glucose tolerance (mean fasting glucose: intrauterine group 5.2(95% confidence interval 5.1 to 5.3), infant group 5.3 (5.1 to 5.5), P=0.94; mean 2 hour glucose: intrauterine group 6.1 (5.8 to 6.4), infant group 6.0 (5.7 to 6.3), P=0.99);(b) insulin concentration; (c) blood pressure; (d)lipid concentration; or (e) coagulation factors. Concentrations of von Willebrand factor were raised in the intrauterine group (156.5 (79.1 to 309.5)) compared with the infant group (127.6 (63.9 to 254.8); P<0.001), and female subjects in the intrauterine group had a stronger interaction between obesity and both systolic (P=0.01) and diastolic (P=0.04) blood pressure than in the infant group. Short adult stature was associated with raised concentrations of glucose and insulin 2 hours after a glucose load—independently of siege exposure. Subjects in the unexposed group had non-systematic differences in subscapular to triceps skinfold ratio, diastolic blood pressure, and clotting factors compared with the exposed groups. Conclusions:Intrauterine malnutrition was not associated with glucose intolerance, dyslipidaemia, hypertension, or cardiovascular disease in adulthood. Subjects exposed to malnutrition showed evidence of endothelial dysfunction and a stronger influence of obesity on blood pressure. Key messages Relations between intrauterine growth and adult disease such as diabetes and cardiovascular disease have been linked to poor nutrition during pregnancy In this study, however, intrauterine exposure to malnutrition was not associated with glucose intolerance Intrauterine malnutrition did not affect insulin concentration, blood pressure, or concentration of lipids or coagulation factors Concentration of von Willebrand factor, a marker of endothelial damage, was raised in the subjects exposed to intrauterine malnutrition Obesity and blood pressure were more strongly related in subjects exposed to intrauterine malnutrition than in subjects either unexposed to malnutrition or exposed to malnutrition only as infants

Endothelial Dysfunction: Cause of the Insulin Resistance Syndrome

Insulin resistance has been proposed as the metabolic basis of atherogenesis. This hypothesis is based on the concept of the “insulin resistance syndrome,” according to which insulin resistance is viewed as the primary abnormality that gives rise to dyslipidemia, essential hypertension, impaired glucose tolerance, and NIDDM. However, this hypothesis takes no account of the wellestablished and central role of vascular endothelium in the atherogenic process. Although endothelial injury is an early and prominent feature of atherogenesis, relatively little attention has been given to its metabolic consequences. In subjects with NIDDM, we have shown that endothelial dysfunction is associated with insulin resistance, raising the question of whether this relationship could be causal. In this article, we review the factors that are considered to be responsible for the development of endothelial dysfunction during atherogenesis, together with the metabolic consequences of endothelial dysfunction. While dysfunction of the endothelium in large and medium-sized arteries plays a central role in atherogenesis, we argue that dysfunction of peripheral vascular endothelium, at arteriolar and capillary level, plays the primary role in the pathogenesis of both insulin resistance and the associated features of the insulin resistance syndrome. We propose that the insulin resistance syndrome, together with many aspects of atherogenesis, can be viewed as the diverse consequences of endothelial dysfunction in different vascular beds. This new and testable hypothesis accounts for both the endothelial and metabolic abnormalities associated with atherogenesis.

Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo

To investigate in vivo adipose tissue production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we determined arteriovenous differences in their levels across abdominal subcutaneous adipose tissue in obese subjects. Subjects had a median (interquartile range) age of 44.5 (27-51.3) yr, body mass index (BMI) of 32.9 (26. 0-46.6) kg/m(2), and %body fat of 42.5 (28.5-51.2) %. Although there was not a significant difference in the arteriovenous concentrations of TNF-alpha (P = 0.073) or sTNFR-II (P = 0.18), the levels of sTNFR-I (P = 0.002) were higher in the vein compared with artery, suggesting adipose tissue production of this soluble receptor. There was a significant arteriovenous difference in IL-6 (P < 0.001) but not in its soluble receptor (P = 0.18). There was no relationship between TNF-alpha levels and adiposity indexes (r(s) = 0.12-0.22, P = not significant); however, levels of both its soluble receptor isomers correlated significantly with BMI and %body fat (sTNFR-I r(s) = 0.42-0.72, P < 0.001; sTNFR-II r(s) = 0.36-0.65, P < 0.05- <0. 001). IL-6 levels correlated significantly with both BMI and %body fat (r(s) = 0.51, P = 0.004, and r(s) = 0.63, P < 0.001), but sIL-6R did not. In conclusion, 1) soluble TNFR-I is produced by adipose tissue, and concentrations of both soluble isoforms correlate with the degree of adiposity, and 2) IL-6, but not its soluble receptor, is produced by adipose tissue and relates to adiposity.To investigate in vivo adipose tissue production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we determined arteriovenous differences in their levels across abdominal subcutaneous adipose tissue in obese subjects. Subjects had a median (interquartile range) age of 44.5 (27-51.3) yr, body mass index (BMI) of 32.9 (26.0-46.6) kg/m2, and %body fat of 42.5 (28.5-51.2) %. Although there was not a significant difference in the arteriovenous concentrations of TNF-α ( P = 0.073) or sTNFR-II ( P = 0.18), the levels of sTNFR-I ( P = 0.002) were higher in the vein compared with artery, suggesting adipose tissue production of this soluble receptor. There was a significant arteriovenous difference in IL-6 ( P < 0.001) but not in its soluble receptor ( P = 0.18). There was no relationship between TNF-α levels and adiposity indexes ( r s = 0.12-0.22, P = not significant); however, levels of both its soluble receptor isomers correlated significantly with BMI and %body fat (sTNFR-I r s = 0.42-0.72, P < 0.001; sTNFR-II r s = 0.36-0.65, P < 0.05- <0.001). IL-6 levels correlated significantly with both BMI and %body fat ( r s = 0.51, P = 0.004, and r s = 0.63, P < 0.001), but sIL-6R did not. In conclusion, 1) soluble TNFR-I is produced by adipose tissue, and concentrations of both soluble isoforms correlate with the degree of adiposity, and 2) IL-6, but not its soluble receptor, is produced by adipose tissue and relates to adiposity.

von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects The Hoorn Study

Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3- and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways.

Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians.

Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers of inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27+/-1 years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r=0.71, 0.57, and 0.51, all P<0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r= -0.65 and -0.46, both P<0.001) and positively correlated with CRP (r=0.46, and 0.33, both P<0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis.

Diabetes care in sub-Saharan Africa

The increasing numbers of people with type 2 diabetes is a worldwide concern. It presents an added challenge in sub-Saharan Africa, where diabetes must compete for resources with communicable diseases. A scarcity of financial resources and appropriate staff mean that many people with type 2 diabetes have complications and that those with type 1 diabetes have an extremely short life-expectancy, whether or not they have been diagnosed with the disorder. We review the current evidence on diabetes care in sub-Saharan Africa and propose an 11-point action plan to address this problem in the region.

Effect of Vitamin C on Glycosylation of Proteins

Twelve nondiabetic subjects consumed 1 g/day vitamin C for 3 mo. A fasting blood sample was taken at the start of the study and at the end of each month for the measurement of plasma and intraerythrocyte glucose, vitamin C, glycosylated hemoglobin (affinity chromatography and electrophoresis), and glycosylated albumin (affinity chromatography). Although there were no significant changes in fasting glycemia, glycosylated hemoglobin (affinity chromatography) decreased 18%, from 6.18 ± 0.48% (mean ± SD) at the start to 5.05 ± 0.50% (P < 0.0001) after 3 mo, whereas, HbA1 measured by electrophoresis increased 16%, from 6.17 ± 0.61 to 7.16 ± 0.59% (P < 0.0001) in this period. Glycosylated albumin decreased 33%, from 1.56 ± 0.24 to 1.04 ± 1.01% (P < 0.0001) after 3 mo. This discrepancy between glycosylated hemoglobin measured by electrophoresis and affinity chromatography was due to methodological differences between the two techniques, with affinity chromatography measuring “true” glycosylated hemoglobin. The greater decrease found with glycosylated albumin was probably due to the different distribution of vitamin C between plasma and within the erythrocyte, levels after 1 mo of supplementation being 109 ± 19 and 59 ± 9 μM, respectively (P < 0.001). This indicates that administration of oral vitamin C may inhibit the glycosylation of proteins in vivo by a competitive mechanism.

Determinants of Plasminogen Activator Inhibitor 1 Activity in Treated NIDDM and Its Relation to a Polymorphism in the Plasminogen Activator Inhibitor 1 Gene

Plasminogen activator inhibitor 1 (PAI-1) activity is increased in patients with non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to their excess risk of cardiovascular disease. We examined the determinants of PAI-1 activity in 146 NIDDM subjects by using specific assays of insulin and intact and des-31,32-proinsulin and measures of insulin resistance, relating these measurements to serum lipids, hypoglycemic therapy, and a common 4G/5G polymorphism in the promoter region of the PAI-1 gene. Subjects were treated with insulin, sulfonylurea, sulfonylurea plus metformin, metformin, and diet alone. In the whole group, PAI-1 activity correlated significantly with serum triglycerides (r = 0.39, P < 0.001), specific insulin (r = 0.29, P < 0.001), intact proinsulin (r = 0.24, P = 0.004), and des-31,32-proinsulin (r = 0.30, P < 0.001) and in subjects not on insulin (n = 110), with insulin sensitivity (r = −0.42, P < 0.001). There was a significant difference in PAI-1 activity among the three genotypic groups (P = 0.016); subjects with the genotype 4G/4G had PAI-1 levels one-third higher than those with the 5G/5G genotype. In the 4G/4G group, PAI-1 activity correlated significantly with triglyceride levels (r = 0.65, P < 0.0001). There was no significant difference in PAI-1 activity in the different treatment groups despite a significant difference in concentrations of intact and des-31,32-proinsulin. In a multiple regression model, insulin sensitivity and the interaction between PAI-1 4G/5G genotype and triglyceride were the strongest determinants of PAI-1 activity.In conclusion, in this sample of NIDDM subjects, the influence of triglyceride on PAI-1 seems to be genotype dependent, and this interaction is a major determinant of PAI-1 activity.

Plasma Thrombin-Activatable Fibrinolysis Inhibitor Antigen Concentration and Genotype in Relation to Myocardial Infarction in the North and South of Europe

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis that decreases plasminogen binding to the fibrin surface. The plasma TAFI concentration is almost entirely genetically determined. We investigated whether plasma TAFI levels and polymorphisms located in the TAFI gene could constitute risk markers of myocardial infarction (MI). Plasma TAFI antigen (Ag) levels were assayed by ELISA and 2 TAFI gene polymorphisms (Ala147Thr and C+1542G in the 3′ untranslated region) were determined in a large European case-control study. This study compared 598 men recruited 3 to 6 months after MI with 653 age-matched controls from North Europe (Stockholm, Sweden, and London, England) and South Europe (Marseilles, France, and San Giovanni Rotondo, Italy). A TAFI Ag value above the 90th percentile was associated with a significantly lower risk of MI (odds ratio 0.55, P <0.02), indicating that elevated TAFI may be protective against MI. As previously shown, the 2 TAFI gene polymorphisms were in strong linkage disequilibrium and were associated with the TAFI Ag concentration, with carriers of the Thr147 and 1542C alleles having higher levels (P <0.0005). These effects were similar in controls and cases and in each center. There was a difference in allele frequency between cases and controls for the Ala147Thr polymorphism, with Thr147 allele carriers being more frequent in controls than in cases in 2 centers, Stockholm (P =0.03) and San Giovanni Rotondo (P =0.03); the odds ratio for the entire cohort was 0.78 (P <0.05). In conclusion, patients with a recent MI presented lower values of TAFI Ag and higher frequencies of the “TAFI-decreasing” alleles. The geographical differences observed do not contribute to explaining the North-South gradient in MI risk in Europe.

The idolatry of the surrogate.

Easier to measure surrogate outcomes are often used instead of patient important outcomes such as death, quality of life, or functional capacity when assessing treatments. John Yudkin, Kasia Lipska, and Victor Montori argue that our obsession with surrogates is damaging patient care