This is a review of research carried out in Japanese Americans that points towards possible approaches to prevention of type 2 diabetes mellitus. The natural history of type 2 diabetes usually includes both insulin resistance and β-cell dysfunction. Insulin secretion may compensate for insulin resistance. Alternatively, enhanced insulin sensitivity may mask an insulin secretory defect. Epidemiological data support the view that in the vast majority of cases of type 2 diabetes, insulin resistance is essential to the pathogenesis of hyperglycemia. Increased diabetes prevalence as ethnic groups migrate to more urban or westernized regions has been attributed to increased occurrence of insulin resistance. Research among Japanese Americans in Seattle, Washington, showed a higher prevalence of type 2 diabetes than in Japan, which suggested that factors associated with ‘westernization’ might be playing a role in bringing out underlying susceptibility to diabetes. Our research has shown that these impressions were correct and that the abnormalities that characterize the metabolic syndrome play a significant role. Due to increased intra-abdominal fat deposition, Japanese Americans were likely to be ‘metabolically obese’ despite relatively normal BMI. A diet higher in animal fat and lower levels of physical activity were risk factors leading to increased intra-abdominal fat deposition, insulin resistance, and diabetes. Information from epidemiological studies such as these may be used to determine whether diabetes may be prevented through changes in lifestyle or application of specific therapies targeted towards identified metabolic abnormalities.

The main purpose of treating diabetes is to prevent chronic complications. Strict glycemic control is known to suppress the occurrence and progression of these complications. The test for plasma glucose is essential to identify diabetic patients, as mild hyperglycemia without symptoms can be a risk factor for complications. The new classification and diagnostic criteria for diabetes were proposed by the American Diabetes Association (ADA), WHO and Japan Diabetes Society (JDS) between 1997 and 1999. Diabetes is classified into four etiological categories; type 1, type 2, diabetes due to other specific mechanisms or conditions, and gestational diabetes. Another classification system according to the degree of metabolic abnormality has also been adopted. For diagnosis of diabetes, the JDS Committee classified the glycemic state into three categories based on fasting plasma glucose (FPG) and 2-h plasma glucose in the 75 g oral glucose tolerance test (2hPG); normal type (FPG <110 and 2hPG <140 mg/dl), diabetic type (FPG <126 and/or 2hPG <200 mg/dl), and borderline type (neither normal nor diabetic type). The borderline type corresponds to the sum of impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) based on ADA and WHO. Using the JDS criteria, diabetes is diagnosed when hyperglycemia of ‘diabetic type’ is confirmed on two or more occasions. ADA recommends the use of FPG alone for the diagnosis of diabetes, but findings from both Japan and Europe indicate that many diabetic subjects would be classified as non-diabetic solely on the FPG test. JDS recommends the use of the glucose tolerance test when the elevation of FPG is mild. Keeping glycemia near-normal by periodic monitoring of glycemic parameters and by appropriate treatment would prevent or reduce the diabetic complications in patients to a minimum.

Diabetes mellitus is one of the most prevalent diseases among adult population in Japan. The persistent hyperglycemia is responsible for the appearance of various organ and tissue damage in diabetic subjects. Eyes, kidneys and peripheral nerves are frequently damaged due to diabetes-specific alteration in microvessels. Furthermore, large vessels are also damaged causing severe diseases such as myocardial infarction, cerebral infarction and gangrene. The pathogenesis of these alterations in small and large vessels has been extensively studied and various metabolic abnormalities induced by hyperglycemia are proposed to play a major role in the development of these diabetic vascular complications. Among those metabolic abnormalities, the activation of the diacyl glycerol-protein kinase C pathway has been proposed to play a pivotal role in the pathogenesis of not only microvascular complications but also macrovascular complications. The beneficial effect of a protein kinase C inhibitor on renal, retinal and atherosclerotic lesions in diabetic animal models may support this notion. The results of several large-scale clinical trials have confirmed the efficacy of glycemic control as well as blood pressure control in the management of diabetic complications. It is a prerequisite, therefore, to obtain near-normal glycemic and blood pressure control in order to prevent the appearance of diabetic complications and also suppress their progression. In this aspect nutritional consideration may be an important way to improve the quality of these managements.

Regular physical exercise has been known to be beneficial in the treatment of type 2 diabetes. Epidemiological studies of physical exercise: previous non-randomized studies suggested that a life-style intervention program involving diet and/or exercise reduced the progression of impaired glucose tolerance (IGT) to type 2 diabetes. Recent randomized controlled intervention trials also showed that diet and/or exercise intervention led to a significant decrease in the incidence of diabetes among those with IGT. Endocrinological and metabolic effects of exercise: in well controlled diabetic patients, physical exercise promotes utilization of blood glucose and lowers blood glucose levels. On the other hand, in poorly controlled diabetic patients with ketosis, physical exercise results in further rises in blood glucose, free fatty acids and ketone body concentrations. Long-term gentle regular jogging increases insulin action in respect of both carbohydrate and lipid metabolism despite no influence on body mass index or maximal oxygen uptake. A significant correlation was observed between DMCR (insulin sensitivity) and average daily steps (P < 0.005) Our recent data suggested that the improvement of insulin action by physical exercise was attributed, at least in part, to the increase in insulin-sensitive GLUT4 (glucose transporter 4) on the plasma membrane in skeletal muscle. In conclusion, as an adjunct to other forms of therapy, mild regular physical exercise will play an important role in primarily preventing type 2 diabetes.

Diet treatment for diabetes requires restriction of the food amount (energy intake). It is desirable that patients have a proper relative consumption of the three main nutrients (proteins, carbohydrates, fats) and also habitually take low-energy foods such as vegetables, mushrooms and seaweeds, etc. as often as possible in each meal. Therefore, we can replace the expression ‘a diet for diabetes’ with ‘a diet for healthy living’. By showing a clinical case of an obese diabetic patient, who succeeded to reduce their body weight, HbA1c and oral agents through diettreatment, and finally could go on diet treatment only, the importance of diet therapy can be emphasized. Furthermore, the estimation index was examined to evaluate how accurately diabetic patients could estimate food energy. According to this study, a large amount of food on the plate leads most patients to underestimate the amount of real energy, and patients are apt to eat too much compared with having smaller amounts of food on the plate. By analyzing questionnaires on the diet therapy of approximately 3000 diabetics, it has been shown that the majority of patients at our hospital recognize that diet therapy is the most important factor in the treatment of diabetes. Interestingly, patients who ate all the food served showed a significantly higher body mass index compared with those who left served food.

Until the 1970s, the Korean economy was dominantly agriculture, but nowadays, less than 10 % of the population lives in a rural area, and it is expected that within a generation the proportion of the population engaged in agriculture will be less than 5 %. The living standard is rising as the national economy benefits from the increased sale of industrial products. The dietary patterns are being changed. The diet has changed from one based predominantly on starch based food such as cereals or roots and vegetables to one in which animal products take great prominence with consequent increases in animal fat and protein. The move from simple unrefined foods to more refined and complex manufactured foods has become commonplace. As a result, the general nutritional situation has been improved. Such improvement, however, has brought about an increase in overnutrition in more affluent sections of the population, whereas dietary inadequacy among the lower socio-economic groups and vulnerable classes still persists. Overall, Korea suffers from both undernutrition and overnutrition. The national school feeding program started in 1953 after the Korean War with the support of UNICEF, CARE, and USAID as a relief food program and is now expanding successfully to a self-supporting nationwide scale. The applied nutrition project in rural areas introduced in 1967 with the support of UNICEF, FAO, WHO, and the Korean government continues successfully to the present day. A national dietary survey has been carried out once a year since 1969, and once every 3 years from 1998. Korean recommended dietary allowances were established in 1962 and have been revised every 5 years. The government intends to establish national dietary guidelines for health promotion and prevention of chronic degenerative diseases. Nutrition education and research are also very important national undertakings.

Anthropological evidence suggests that regional differences in eating practices may be characterized by sub-ethnicity. Hakka is one sub-ethnicity who still retain a unique way of life in China. A field survey on diet and health among the Hakka people was undertaken in 1994. Approximately 200 participants were interviewed for their medical history, life-style and food habits. Blood pressure, body mass index, blood sample, 24 h urine and electrocardiogram were collected. The food samples taken from one tenth of the participants were analyzed for the ingredients in their daily meals. From this survey the prevalence of hypertension in Hakka was approximately 10%. The sodium/potassium ratio was lower than that in Guangzhou and comparable with that in Okinawa, the island of longevity in Japan. For men, taurine level was found to be close to that in Mediterranean countries, where there is low mortality from cardiovascular diseases. For women, the taurine level was even higher, approximating that of Japanese women, who show the greatest longevity and lowest cardiac mortality worldwide. Less obesity was found in Hakka people than that in the US, Canada or Japan. These findings suggest that the following are the major reasons for these positive findings: the Hakka people maintain traditional food habits and maintain active awareness of their health; the major foods are rice, fish, vegetables and fruits; wide use of soybeans; extensive consumption of visceral organs which have rich source of trace elements. These eating practices and nutritional patterns may be beneficial factors for preventing atherosclerosis and hypertension.

Mortality statistics from the WHO database covering the period 1960 to 1990 have provided intriguing evidence that something unusual has been affecting in a beneficial way the health of the Mediterranean population. In recent papers, which evaluated the evidence accumulated over the last three decades, it was concluded that the traditional Mediterranean diet meets several important criteria for a healthy diet. Direct evidence in support of the beneficial properties of the Mediterranean diet has also become available. These data were derived from three studies, which have used a diet score, devised a priori on the basis of eight desirable key features of the traditional common diet in the Mediterranean region. The conclusion of these studies is that a diet that adheres to the principles of the traditional Mediterranean one is associated with longer survival. The Greek version of the Mediterranean diet is dominated by the consumption of olive oil and by high consumption of vegetables and fruits. Antioxidants represent a common element in these foods and an antioxidant action provides a plausible explanation for the apparent benefits. Wild edible greens frequently eaten in rural Greece in the form of salads and pies contain very high quantities of flavonoids — considerably higher than those found in red wine or black tea. While there is no direct evidence that these antioxidants are central to the benefits of the Mediterranean Diet, indirect evidence from epidemiological data and the increasing understanding of their mechanisms of action suggest that antioxidants may play a major role.

The importance attributed to dietary change as a means of helping to achieve the major goals of the UK's public health policy as articulated in the Health of the Nation White paper (Department of Health, 1992) is less apparent in the most recent strategy document (Department of Health, 1999). Greater emphasis is given to amelioration of the socio-economic circumstances that are believed to contribute to inequalities in health. Better understanding of the elements of foods and diets which help protect health together with better evidence of effective dietary interventions are essential if the opportunities to use diet to reduce the burden of noncommunicable diseases are to be realised. This is likely to need new research strategies that take advantage of emerging information from genomics and proteomics to produce evidence of safety, efficacy and applicability. Ethical exploitation of the rapid growth in interest in ‘functional foods’ by the food industry will require a level of investment in biomedical research unusual in the past.

Cellular retinol-binding protein, type II (CRBPII) is abundantly expressed in the small intestinal epithelial cells and plays a pivotal role in intestinal absorption and metabolism of retinol and β-carotene. In the 5′-flanking region of rat CRBPII gene, two DR-1 type elements which consist of a direct repeat of the AGGTCA-like motif spaced by a single nucleotide have been identified as putative binding sites for a heterodimer of peroxisome proliferator-activated receptor (PPAR) and retinoid X-receptor (RXR). We found that CRBPII levels were elevated in the residual jejunal segment of rats subjected to jejunal bypass operation, where a concomitant increase in the apoprotein B levels occurred. This result suggested that CRBPII expression was enhanced by a condition where fat absorption was stimulated. Indeed, dietary fat (especially unsaturated fatty acids) has been shown to induce CRBPII gene expression in the jejunum. Nuclear run-on assays revealed that this increase of CRBPII mRNA levels by a high-fat diet was the result of the induction of the gene transcription through the rise in PPARα expression level as well as the increase in its ligand levels. Electrophoretic mobility shift assay using the DR-1 type cis-elements of CRBP II gene showed that PPARα-RXRα heterodimer was capable of binding to these elements, and that nuclear extracts from the jejunum of rats fed the high-fat diet gave greater density of retarded bands than those of rats fed a fat-free diet. We also found that the expression of PPARδ was rather reduced by dietary fat. Thus, CRBPII gene expression is regulated predominantly by dietary fatty acids.

The peroxisome proliferator-activated receptor gamma (PPARγ) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARγ is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARγ in obesity and diabetes.

Nuclear receptors for vitamins A and D belong to the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors. Therefore, most of the biological actions of vitamins A and D are now considered to be exerted through nuclear vitamin receptor-mediated gene expression. The vitamin A nuclear receptors compromise six members, three all-trans retinoic acid receptors (RARα, RARβ, RARγ) and three 9-cis retinoic acid receptors (RXRα, RXRβ, RXRγ) (Mangelsdorf et al. 1995). Unlike vitamin A receptors, only one member is identified for vitamin D. The present study investigating the vitamin D receptor function in gene expression in both cell culture and intact animals was undertaken to better understand the actions of the fat-soluble vitamin A and vitamin D at a molecular level.

The biological role of peroxisome proliferator-activated receptor γ (PPARγ) was investigated by gene targeting and case±control study of the Pro12Ala PPARγ2 polymorphism. Homozygous PPARγ-deficient embryos died at 10.5–11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-deficient mice showed over-expression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARγ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARγ. A Pro12Ala polymorphism has been detected in the human PPARγ2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARγ, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case±control study of the Pro12Ala PPARγ2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that in both mice and humans, PPARg is a thrifty gene mediating type 2 diabetes.

Protein metabolism of growing animals is greatly affected by quantity and nutritional quality of dietary proteins. When animals are fed diets that contain enough proteins of good nutritional quality, they grow well. However, if they are fed diets deficient in protein or in some essential amino acids, their growth rate is markedly depressed. In this paper, we review the response of plasma insulin-like growth factor-I (IGF-I) to quantity and nutritional quality of dietary proteins. The sound correlation between plasma IGF-I concentration and the gain or loss of body proteins under various nutritional conditions suggests that the plasma IGF-I most possibly regulates the growth rate of animals or the rate of whole body protein synthesis. The quantity and nutritional quality of dietary proteins also regulates plasma concentration of IGF-binding proteins (IGFBPs). The changes in plasma concentration of IGFBPs presumably modifies the activity of IGF-I to regulate whole body protein synthesis. Molecular mechanisms of the changes in plasma concentrations of IGF-I and IGFBPs as affected by dietary proteins are also reviewed.

To explore the underlying molecular mechanism whereby nutrients modulate the expression of intestinal digestion/absorption-related genes, we have cloned the 5′ flanking regions of two representing disaccharidase genes, i.e. sucrase–isomaltase (SI) and lactase–phlorizin hydrolase (LPH), and investigated whether the binding activity of putative common nuclear factor(s) binding to the cis-elements located in these regions is altered by dietary manipulations. Orogastric feeding of a sucrose-containing diet to rats caused parallel increases in SI mRNA and LPH mRNA levels within 3 h. Among the monosaccharides tested, fructose gave rise to the most prominent increase in the mRNA levels of SI and LPH genes, which were accompanied by a coordinate rise in the mRNA levels of two microvillar hexose transporters, i.e. SGLT1 and GLUT5. Nuclear run-on assays revealed that fructose, but not glucose, increased the transcription of SI, LPH and GLUT5. DNase I footprinting analysis of the rat LPH gene showed that the protected region conserved the same sequence as the cis-element (CE-LPH1) reported in the pig LPH gene. Electrophoretic mobility shift assay using CE-LPH1 and the related cis-element of SI gene (SIF1) revealed that nuclear extracts from the jejunum of rats fed the high-starch diet gave greater density of retarded bands than those of rats fed the low-starch diet. Force feeding a fructose diet gave rise to an increase in the binding of the dimeric nuclear protein (Cdx-2) to the SIF1 element. These results suggest that the cis-elements of CE-LPH1 and SIF1 might be involved in the carbohydrate-induced increases of the transcription of LPH and SI, presumably through a change in the expression and/or binding activity of Cdx-2.