C. Nicholas Hales

Lifespan: Catch-up growth and obesity in male mice

Poor fetal growth is linked with long-term detrimental effects on health in adulthood. Here we investigate whether the lifespan of male mice is affected by their growth rate when they were suckling and find that limiting growth during that period not only increases longevity but also protects against the life-shortening effect of an obesity-inducing diet later on. By contrast, we find that lifespan is considerably shortened if the postnatal period of growth is accelerated to make up for reduced growth in utero, and that, in addition, these mice are susceptible to the adverse effects on longevity of an obesity-inducing diet after weaning.

THE SULPHONYLUREA RECEPTOR MAY BE AN ATP-SENSITIVE POTASSIUM CHANNEL

The stimulation of insulin secretion from the beta cells of the islets of Langerhans appears to be mediated by a decrease in the cell-membrane potassium-ion permeability. Tolbutamide reduced K+ movement through an ATP-sensitive K+ channel in patches of plasma membrane from an insulin-producing cell line when applied to the external surface of the membrane. The effect occurred at concentrations which exist in the serum of patients treated with tolbutamide and which stimulate insulin secretion from islets of Langerhans in vitro. Glibenclamide had a similar effect but, in keeping with its greater therapeutic potency, at concentrations one hundred times lower. These findings suggest that an ATP-sensitive K+ channel or a protein closely associated with it may be the receptor through which sulphonylureas act to stimulate insulin secretion in vitro.

INSULIN DEFICIENCY IN NON-INSULIN-DEPENDENT DIABETES

A highly specific two-site immunoradiometric assay for insulin was used to measure the plasma insulin response to 75 g glucose administered orally to 49 patients with non-insulin-dependent diabetes (NIDDM). The plasma insulin concentration 30 min after glucose ingestion was lower in the diabetic patients than in matched controls for both non-obese (11-83 pmol/l vs 136-297 pmol/l, p less than 0.01) and obese subjects (23-119 pmol/l vs 137-378 pmol/l, p less than 0.01). By means of another two-site immunoradiometric assay, the basal intact proinsulin level was found to be higher in the NIDDM patients than in the controls for both non-obese (7.1 [SEM 1.2] pmol/l vs 2.4 [0.4] pmol/l, p less than 0.01) and obese subjects (14.4 [2.2] pmol/l vs 5.9 [1.9] pmol/l, p less than 0.01). The basal level of 32-33 split proinsulin was also raised in NIDDM. Previous failure to show clear separation between normal and NIDDM insulin responses was probably due to the high concentrations of proinsulin-like molecules in the plasma of NIDDM patients. These substances cross-react as insulin in most, if not all, insulin radioimmunoassays but have very little biological insulin-like activity. It is therefore now possible and necessary to designate most NIDDM patients as insulin deficient.

Diabetes in Old Male Offspring of Rat Dams Fed a Reduced Protein Diet

Restricted fetal growth is associated with increased risk for the future development of Type 2 diabetes in humans. The study aim was to assess the glucose tolerance of old (seventeen months) male rats, which were growth restricted in early life due to maternal protein restriction during gestation and lactation. Rat mothers were fed diets containing either 20% or 8% protein and all offspring weaned onto a standard rat diet. In old-age fasting plasma glucose concentrations were significantly higher in the low protein offspring: 8.4 (1.3)mmol/l v. 5.3 (1.3)mmol/l (p = 0.005), Areas under the curves were increased by 67% for glucose (p = 0.01) and 81% for insulin (p = 0.01) in these rats in intravenous glucose tolerance tests, suggesting (a degree of) insulin resistance. These results show that early growth retardation due to maternal protein restriction leads to the development of diabetes in old male rat offspring. The diabetes is predominantly associated with insulin resistance.

Early programming of glucose-insulin metabolism.

Epidemiological studies have revealed strong inverse relationships between birthweight and the risk of developing type 2 diabetes mellitus (T2DM) and the metabolic syndrome. The mechanistic basis of these relationships remains the subject of research and debate. Evidence for the importance of the fetal environment has been obtained from both human and rodent studies. Studies of monozygotic twins have shown that genetic effects cannot explain these relationships entirely, if at all. Fetal and early postnatal growth restriction produced by feeding a reduced protein diet to rat dams leads to T2DM in old male offspring and, if combined with an obesity-inducing diet after weaning, to all the features of the metabolic syndrome.

Early programming of weight gain in mice prevents the induction of obesity by a highly palatable diet.

Poor early growth is associated with Type II diabetes, hypertension and other features of the metabolic syndrome in adulthood. It has been suggested that this results from the development of a thrifty phenotype by a malnourished fetus. Such a phenotype would predispose the offspring to the development of obesity if born into conditions of over-nutrition. The present study aimed to determine if early nutrition affected subsequent development of obesity. Mice were established as follows: (a) controls (offspring of control dams), (b) recuperated (offspring of dams fed a low-protein diet during pregnancy, but nursed by control dams) and (c) postnatal low-protein (offspring of control dams nursed by low-protein-fed dams). Mice were weaned on to standard laboratory chow or a cafeteria diet. Recuperated offspring, although smaller at birth ( P <0.01), caught up and exceeded the weight of control offspring by 7 days of age ( P <0.001). Postnatal low-protein offspring were smaller than controls by 7 days of age ( P <0.001). Recuperated animals gained more weight than controls when given free access to a highly palatable diet ( P <0.01). Postnatal low-protein animals showed no additional weight gain when given a highly palatable diet compared with chow-fed litter-mates. These results suggest that the early environment has long-term consequences for weight gain. These programmed responses are powerful enough to block excess weight gain from a highly palatable diet and, thus, have major implications for the drug-free regulation of food intake and obesity.

Proinsulin Is an Independent Predictor of Coronary Heart Disease Report From a 27-Year Follow-Up Study

Background—Some, but not all, studies have reported a relationship between plasma insulin and coronary heart disease (CHD). Conventional nonspecific insulin assays are also measuring various fractions of proinsulin-like molecules due to cross-reactivity. The long-term relationship between proinsulin-like molecules and CHD is largely unknown. For this reason, the longitudinal relationships between intact proinsulin, split proinsulin, specific insulin, immunoreactive insulin, and CHD, were studied in a population-based cohort of 50-year-old men (n=874), with a follow-up of 27 years. Methods and Results—Fasting proinsulin-like molecule and specific-insulin concentrations were measured in plasma (stored frozen since baseline 1970 to 1973) by specific 2-site immunometric assays. Immunoreactive insulin concentrations were determined at baseline. The associations between proinsulin-like molecules, specific insulin, immunoreactive insulin, and CHD mortality (International Classification of Diseases [9th revision] codes 410 to 414) were analyzed using Cox’s proportional hazards regression and presented as hazard ratios (HRs) with their 95% confidence intervals (CIs) for a 1-SD increase in a predictor variable. In the univariate analysis, intact proinsulin (HR, 1.69; 95% CI, 1.41 to 2.01) was the strongest predictor of death from CHD. In the multivariate analysis, smoking (HR, 1.57; 95% CI, 1.03 to 2.38), intact proinsulin (HR, 1.47; 95% CI, 1.18 to 1.82), systolic blood pressure (HR, 1.38; 95% CI, 1.14 to 1.66), and LDL/HDL cholesterol ratio (HR, 1.31; 95% CI, 1.12 to 1.53) were independent predictors of CHD mortality (adjusted for body mass index, triglycerides, and fasting glucose), whereas specific insulin and immunoreactive insulin were not (HR, 1.12; 95% CI, 0.90 to 1.40). The increased risk was restricted to the upper third of the proinsulin distribution. Conclusion—Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.

Frequent Salad Vegetable Consumption Is Associated with A Reduction in the Risk of Diabetes Mellitus

This cross-sectional study was undertaken to investigate the association between the reported frequency of consumption of vegetables and fruits, the choice of staple carbohydrate, and glucose intolerance. One thousand one hundred twenty-two subjects aged 40-64 years in a population-based study underwent an oral glucose tolerance test, and their food consumption was assessed using a food-frequency questionnaire. The crude prevalence of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) was 4.5%, and that of impaired glucose tolerance (IGT) 16.8%. The age-standardized prevalence rates were 2.3 and 11.2%, respectively. Frequent consumption of vegetables throughout the year was inversely associated with the risk of having NIDDM (odds ratio [OR] = 0.16; 95% confidence interval [CI] = 0.04-0.69). This association was maintained after adjustment for age, gender, and family history. Vegetable consumption during the summer months had a much weaker inverse association with the risk of having NIDDM that failed to reach statistical significance. A nonsignificant inverse association between frequent consumption of fruits and NIDDM was observed. Frequent self-reported pasta and rice consumption was associated with a reduction in the risk of having IGT and NIDDM. (OR = 0.62, 95% CI = 0.44-0.87, and OR = 0.51, 95% CI = 0.27-0.99, respectively) but this relationship was not independent of age. Whether these associations reflect specific effects of particular nutrients or are a reflection of the patterning of lifestyle factors remains to be determined.

The electron microscopic localization of cations to pancreatic islets of langerhans and their possible role in insulin secretion

Earlier antimonate techniques for electron microscopic localization of sodium were applied to isolated islets of Langerhans obtained by partial collagenase digestion of mouse and rabbit pancreas. Incubation of islets in low or high glucose media followed by fixation in either (a) glutaraldehyde-osmium-antimonate mixtures or (b) osmium-antimonate mixtures resulted in deposition of precipitation particles in association with organelles directly involved in insulin secretion: beta granules (saccules) and cell membranes. Precipitation particles increased at these two cell sites following glucose incubation. X-ray microprobe analysis of precipitation particles using the AEI-EMMA-4 analytical microscope revealed the presence of other ions in addition to sodium, confirming the nonspecific nature of the antimonate technique. The predominant cation associated with the beta granule saccule and cell membrane was calcium, and the increased precipitation following glucose stimulation suggests an active role of this cation in the insulin secretion process as proposed earlier by biochemical methods.

Poor fetal growth followed by rapid postnatal catch-up growth leads to premature death.

It is widely accepted that individuals with a low birth weight are at increased risk of developing type 2 diabetes, insulin resistance and cardiovascular disease. This risk is amplified if the poor fetal growth is followed by rapid postnatal catch-up growth. We have shown recently that poor fetal growth, resulting from maternal protein restriction, followed by postnatal catch-up growth is associated with reduced average longevity in mice. Here, we show that in addition to reduced average longevity, mice which have been growth restricted in utero and then grown rapidly during the lactation period have a reduced maximum longevity. Maximum longevity of these mice was, further, reduced when the animals were weaned onto an obesity-inducing cafeteria-style diet. This reduced maximum longevity was associated with early age-related weight loss. These results demonstrate that maternal nutrition during critical periods of development has a major impact on quantity as well as quality of life.