Vitamin D and cardiometabolic risk factors and diseases.

Obesity, type 2 diabetes, and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. Insulin resistance, which is a shared feature in these conditions, is also strongly linked to the development of polycystic ovary syndrome (PCOS), which is the most common endocrine disease in women of reproductive age and a major cause of infertility. Vitamin D deficiency has reached epidemic proportions worldwide, primarily due to the shift to sedentary, indoor lifestyles and sun avoidance behaviours to protect against skin cancer. In recent years, vitamin D deficiency has been implicated in the aetiology of type 2 diabetes, PCOS and CVD, and has been shown to be associated with their risk factors including obesity, insulin resistance, hypertension, as well as chronic low-grade inflammation. Treating vitamin D deficiency may offer a feasible and cost-effective means of reducing cardiometabolic risk factors at a population level in order to prevent the development of type 2 diabetes and CVD. However, not all intervention studies show that vitamin D supplementation alleviates these risk factors. Importantly, there is significant heterogeneity in existing studies with regards to doses and drug regimens used, populations studied (i.e. vitamin D deficient or sufficient), and the lengths of supplementation, and only few studies have directly examined the effect of vitamin D on insulin secretion and resistance with the use of clamp methods. Therefore, there is a need for well-designed large scale trials to clarify the role of vitamin D supplementation in the prevention of type 2 diabetes, PCOS, and CVD.

Diagnostic thresholds for diabetes: the association of retinopathy and albuminuria with glycaemia.

AIM: We examined the association of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG) and HbA1c with retinopathy and microalbuminuria using both deciles of glycaemia and change point models, to validate current diagnostic criteria for diabetes and to identify therapeutic thresholds for glycaemic control. METHODS: The Australian Diabetes Obesity and Lifestyle study (AusDiab), conducted in 1999-2000, included adults aged > or =25 years from 42 randomly selected areas of Australia. Retinopathy and albuminuria were assessed in participants identified as having diabetes (based on self report and oral glucose tolerance test), impaired fasting glucose, impaired glucose tolerance and in a random sample with normal glucose tolerance. Data were available for 2,182 participants with retinal photographs and 2,389 with urinary albumin/creatinine results. RESULTS: The prevalence of retinopathy in the first 8 deciles of FPG and HbA1c and the first 9 deciles of 2hPG were 7.2, 6.6, and 6.3%, respectively and showed no variation with increasing glucose or HbA1c. Above these levels, the prevalence rose markedly to 18.6% in the top 2 deciles of FPG, 21.3% in the top 2 deciles of HbA1c and 10.9% in the top decile of 2hPG. The thresholds for increasing prevalence of retinopathy were 7.1 mmol/l for FPG, 6.1% for HbA1c and 13.1 mmol/l for 2hPG. The prevalence of microalbuminuria rose gradually across deciles of each glycaemic measure. Thresholds were less clear than for retinopathy, but were seen at a FPG of 7.2 mmol/l and HbA1c of 6.1%, with no evidence of a threshold effect for 2hPG. CONCLUSIONS: The prevalence of retinopathy rose dramatically in the highest deciles of each glycaemic measure, while for microalbuminuria the increase of prevalence was more gradual. The FPG values corresponded well with the WHO diagnostic cut-point for diabetes, however the 2hPG value did not. HbA1c thresholds were similar for both retinopathy and microalbuminuria and compared well to values shown in other studies. These results support current targets for FPG and HbA1c in preventing microvascular complications.

Gender differences in the prevalence of impaired fasting glycaemia and impaired glucose tolerance in Mauritius. Does sex matter?

OBJECTIVE: To examine gender differences in the characteristics and prevalence of various categories of glucose tolerance in a population study in Mauritius. RESEARCH DESIGN AND METHODS: In 1998, a community-based cross-sectional survey was conducted in Mauritius. Categories of glucose metabolism were determined in 5388 adults, with an oral glucose tolerance test given to those who did not have previously diagnosed diabetes (n=4036). Other cardiovascular risk factors were assessed among those without known diabetes. RESULTS: For men and women the prevalence of diabetes (22.0 vs. 21.8%, respectively) and the prevalence of coexisting impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (3.2 vs. 2.9%) were similar. However, men were twice as likely as women to have isolated IFG [5.1% (4.2-6.0) vs. 2.9% (2.3-3.5)], despite being younger, thinner and with lower plasma insulin but higher lipids. Conversely, the prevalence of isolated IGT was lower in men [9.0% (7.9-10.2) vs. 13.9% (12.6-15.1)]. Among non-diabetic individuals, fasting glucose was higher in men than women, whereas 2-h glucose was higher in women. In people without diabetes, women had significantly higher body mass index, beta cell function (HOMA-B), fasting and 2-h insulin than men and significantly lower waist-hip ratios, waist circumference, insulin sensitivity (HOMA-S) and triglycerides. CONCLUSION: In Mauritius, the distribution of impaired glucose metabolism differs by sex. The observation that IFG is more prevalent in men and IGT more prevalent in women raises important questions about their underlying aetiology and the ability of the current glucose thresholds to equally identify men and women at high-risk of developing diabetes. IFG should be seen as a complimentary category of abnormal glucose tolerance, rather than a replacement for IGT.

Foot complications in Type 2 diabetes: an Australian population-based study.

AIMS: To determine the prevalence and risk factors for neuropathy and peripheral vascular disease (PVD) in the Australian diabetic population and identify those at high risk of foot ulceration. METHODS: The Australian Diabetes Obesity and Lifestyle study included 11 247 adults aged >or= 25 years in 42 randomly selected areas of Australia. Neuropathy and PVD were assessed in participants identified as having diabetes (based on self report and oral glucose tolerance test), impaired fasting glucose, impaired glucose tolerance and in a random sample with normal glucose tolerance (total n = 2436). RESULTS: The prevalence of peripheral neuropathy was 13.1% in those with known diabetes (KDM) and 7.1% in those with newly diagnosed (NDM). The prevalence of PVD was 13.9% in KDM and 6.9% in NDM. Of those with diabetes, 19.6% were at risk of foot ulceration. Independent risk factors for peripheral neuropathy were diabetes duration (odds ratio (95% CI) 1.73 (1.33-2.28) per 10 years), height (1.42 (1.08-1.88) per 10 cm), age (2.57 (1.94-3.40) per 10 years) and uric acid (1.59 (1.21-2.09) per 0.1 mmol/l). Risk factors for PVD were diabetes duration (1.64 (1.25-2.16) per 10 years), age (2.45 (1.86-3.22) per 10 years), smoking (2.07 (1.00-4.28)), uric acid (1.03 (1.00-1.06) per 0.1 mmol/l) and urinary albumin/creatinine ratio (1.11 (1.01-1.21) per 1 mg/mmol). CONCLUSIONS: The prevalence of neuropathy and PVD was lower in this population than has been reported in other populations. This may reflect differences in sampling methods between community and hospital-based populations. Nevertheless, a substantial proportion of the diabetic population had risk factors for foot ulceration.

Association of physical activity and serum insulin concentrations in two populations at high risk for type 2 diabetes but differing by BMI.

OBJECTIVE: Physical activity and insulin sensitivity are related in epidemiological studies, but the consistency of this finding among populations that greatly differ in body size is uncertain. The present multiethnic epidemiological study examined whether physical activity was related to insulin concentrations in two populations at high risk for diabetes that greatly differ by location, ethnic group, and BMI. RESEARCH DESIGN AND METHODS: The study populations consisted of 2,321 nondiabetic Pima Indian men and women aged 15-59 years from Arizona and 2,716 nondiabetic men and women aged 35-54 years from Mauritius. Insulin sensitivity was estimated by mean insulin concentration (average of the fasting and postload insulin), and total (i.e., leisure and occupational) physical activity was assessed by questionnaire. RESULTS: Pima men and women who were more active had significantly (P < 0.05) lower mean insulin concentrations than those less active (BMI and age-adjusted means were 179 vs. 200 and 237 vs. 268 pmol/l). Similar findings were noted in Mauritian men and women (94 vs. 122 and 127 vs. 148 pmol/l). In both populations, activity remained significantly associated with mean insulin concentration controlled for age, BMI, waist-to-thigh or waist-to-hip ratio, and mean glucose concentrations. CONCLUSIONS: Physical activity was negatively associated with insulin concentrations both in the Pima Indians, who tend to be overweight, and in Mauritians, who are leaner. These findings suggest a beneficial role of activity on insulin sensitivity that is separate from any influence of activity on body composition.

Decreasing prevalence of cigarette smoking in the middle income country of Mauritius: questionnaire survey.

OBJECTIVES: To describe changes in the prevalence of cigarette smoking in the middle income country of Mauritius from 1987 to 1998, and to relate these changes to legislative and health promotion efforts over the same period. DESIGN: Questionnaire survey. SETTING: Mauritius, an island in the Indian Ocean with a population of about 1.2 million (about 70% south Asian, 2% Chinese, and 28% Creole). PARTICIPANTS: Data were obtained from 5072 participants in 1987, 6573 in 1992, and 6281 in 1998. MAIN OUTCOME MEASURES: Prevalence of current smoking in 1987, 1992, and 1998, sales of cigarettes in Mauritius, and information on activities for control of tobacco. RESULTS: Self reported cigarette smoking has been decreasing in Mauritius since 1987, with the largest decrease between 1987 and 1992. From 1987 to 1998 smoking prevalence decreased by 23% in men and 61% in women. Smoking decreased across all age and ethnic groups and across different levels of income and education. Sales of cigarettes also decreased in line with smoking prevalence. CONCLUSIONS: The introduction of cigarette taxes, a limited health promotion programme, and the absence of massive promotional campaigns by the sole tobacco company on Mauritius have led to a striking and continued decrease in smoking prevalence and cigarette consumption on the island.

Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males.

OBJECTIVE: To investigate the relationship between polymorphisms in the OB-R and OB genes and metabolic markers for obesity and glucose intolerance in a population of Nauruan men. In addition, we examined the effect of the simultaneous presence of the three polymorphisms on the phenotype of individuals in this population. DESIGN AND SUBJECTS: This study was conducted in a population from the Pacific Island of Nauru. Populations in this region have some of the highest recorded rates of obesity and type 2 diabetes and are therefore of great interest in the genetic analysis of these diseases. Two hundred and thirty-two male subjects were examined in this cross-sectional study. All subjects were non-diabetic and the group had a mean age of 31 y and a mean body weight of 104 kg. MEASUREMENTS: Several phenotypic measures of body fatness and fat distribution (anthropometry), fasting plasma insulin, glucose and leptin concentrations, blood pressure and 2 h plasma glucose concentration, genotypes of subjects for the Gln223Arg, PRO1019pro (OB-R gene) and OB gene polymorphisms. RESULTS: Individually, the OB gene and Gln223Arg OB-R polymorphisms were not associated with the obese or glucose-intolerant phenotype in this population. Individuals with the PRO1019pro polymorphism were found to have elevated insulin concentrations and diastolic blood pressure (Pc = 0.04). In addition, individuals found to simultaneously exhibit homozygosity of the common allele of all three polymorphisms (genotypes: Arg/Arg, pro/pro and II/II) exhibited significantly elevated fasting insulin levels (Pc = 0.03). CONCLUSIONS: Pacific Island populations exhibit a remarkably high prevalence rate of obesity and type 2 diabetes and represent a unique population for genetic studies of obesity. In the present study we have revealed that a specific combination of alleles in OB and OB-R, two candidate genes for obesity, may confer an increased risk for the development of insulin resistance in Nauruan males.

Rapid actions of insulin on sensory nerve function.

The acute action of insulin on neurogenic flare was investigated using iontophoresis. Twenty-five patients with insulin-dependent diabetes mellitus (IDDM) and 25 age- and gender-matched controls were studied. Axon reflex vasodilatation was evoked by transdermal iontophoresis of acetylcholine (ACh) before and after skin treatment by the iontophoresis of insulin and measured using laser Doppler velocimetry. Axon reflex responses were reduced in IDDM patients compared with controls (p< 0.001) but were restored after the iontophoresis of insulin. Insulin iontophoresis had no effect on the size of the axon reflex response in control subjects (p > 0.05). This study confirms the reduction of the ACh-induced flare in human patients with IDDM and has demonstrated relatively rapid effects of insulin on this cutaneous neurogenic response.

Do leptin levels predict weight gain?--A 5-year follow-up study in Mauritius. Mauritius Non-communicable Disease Study Group.

OBJECTIVE: To investigate whether relative baseline leptin levels predict long-term changes in adiposity and/or its distribution. RESEARCH METHODS AND PROCEDURES: In a longitudinal study of 2888 nondiabetic Mauritians aged 25 years to 74 years who participated in population-based surveys in 1987 and 1992, changes in body mass index (BMI), waist/hip ratio (WHR), and waist circumference were compared between "hyperleptinemic," "normoleptinemic," and "hypoleptinemic" groups. "Relative leptin levels" were calculated as standardized residuals from the regression of log10 leptin on baseline BMI to provide a leptin measure independent of BMI. Analyses were performed within each sex. A linear regression model was used to assess the effect of standardized residuals on changes in BMI, WHR, and waist circumference, independent of baseline BMI, age, fasting insulin, and ethnicity. RESULTS: After adjusting for age and baseline BMI by analysis of covariance, there was no difference in changes in BMI, WHR, or waist circumference between men with low, normal, or high relative leptin levels. Among women, there was a significant difference in deltaWHR across leptin groups, such that the largest increase occurred in the "normal" leptin group. For both men and women, the linear regression models explained approximately 10% of variation in dependent variables, and the only significant independent variables were age, BMI, and being of Chinese origin, compared with Indian origin. DISCUSSION: These findings do not support a role for leptin concentration in predicting weight gain or changes in fat distribution in adults over a 5-year period.

The relationship of menstrual irregularity to type 2 diabetes in Pima Indian women.

OBJECTIVE: Menstrual irregularity is associated with hyperinsulinemia and hyperandrogenemia in nondiabetic Pima Indian women of child-bearing age. In this population-based study, we determined the relationship of menstrual irregularity to type 2 diabetes in Pima Indian women. RESEARCH DESIGN AND METHODS: Participants for this cross-sectional analysis were 695 nonpregnant Pima Indian women, aged 18-44 years, involved in an ongoing epidemiologic study of diabetes among residents of the Gila River Indian Community of Arizona. Clinical data were collected by questionnaire and an examination that included a 75-g oral glucose tolerance test; diabetes was diagnosed by World Health Organization criteria. Menstrual irregularity was defined as an interval of 3 months or more between menses, when not pregnant, since age 18 years. RESULTS: History of menstrual irregularity was significantly associated with a high prevalence of diabetes (37 vs. 13%; odds ratio = 4.2, 95% CI = 1.6-10.8) in the least obese women (BMI < 30 kg/m2), adjusted for the effects of age and overall obesity. This association was, in part, because of greater central obesity in women with irregular menses. In more obese women, there was little association with menstrual irregularity, and diabetes was frequent regardless of menstrual history. CONCLUSIONS: Prevalence of type 2 diabetes is higher among Pima indian women with a history of menstrual irregularity. The difference is most pronounced among the least obese group of women. This association may be because of insulin resistance and hyperinsulinemia, which predict type 2 diabetes, also causing hyperandrogenism and menstrual irregularity. The findings reinforce the need to evaluate women with menstrual irregularity for hyperglycemia.

Is there a relationship between leptin and insulin sensitivity independent of obesity? A population-based study in the Indian Ocean nation of Mauritius. Mauritius NCD Study Group.

OBJECTIVE: It has been shown previously in smaller studies that fasting serum leptin and insulin concentrations are highly correlated, and insulin sensitive men have lower leptin levels than insulin resistant men matched for fat mass. We have examined the association between insulin resistance (assessed by fasting insulin) and leptin after controlling for overall and central adiposity in a population-based cohort. DESIGN: Leptin levels were compared across insulin resistance quartiles within three categories of obesity (tertiles of body mass index (BMI)). Partial correlation coefficents and multiple linear regression models were used to assess the relationship between leptin and fasting insulin after adjusting for BMI and waist to hip ratio (WHR) or waist circumference. SUBJECTS: Subjects were normoglycemic participants of a 1987 non-communicable diseases survey conducted in the multiethnic population of Mauritius. 1227 men and 1310 women of Asian Indian, Creole and Chinese ethnicity had normal glucose tolerance and fasting serum leptin measurements. RESULTS: Mean serum leptin concentration increased across quartiles of fasting insulin in each BMI group and gender, after controlling for BMI, WHR and age. Furthermore, fasting insulin was a significant determinant of serum leptin concentration, independent of BMI and WHR, in both men and women. Similar results were found if waist circumference replaced BMI and WHR in the model. CONCLUSION: These results suggest that insulin resistance/concentration may contribute to the relatively wide variation in leptin levels seen at similar levels of body mass or alternatively, leptin may play a role in the etiology of insulin resistance. Further studies will be important to determine whether the hyperleptinemia/insulin resistance relationship has a role in the natural history of obesity, Type 2 diabetes mellitus and the other metabolic abnormalities associated with insulin resistance.

Associations among physical activity, television watching, and obesity in adult Pima Indians.

It has been suggested that television watching and physical activity are related to obesity. This association, however, has been investigated mainly in children. This study provided the opportunity to examine the relationship between television watching, physical activity, and body mass index in adult Pima Indians, a population with a high prevalence of obesity. Hours per day of television watched, past-year physical levels (MET-h/wk; leisure and occupational combined) and BMI (kg.m-2) were measured in 2452 men and women subjects 21-59 yr old. In adults between the ages of 21 and 39 yr, TV and physical activity levels were negatively correlated (r = -0.11 for men and -0.10 for women). Weaker associations were found between TV and BMI (r = 0.08 for men and 0.04 for women). There were no significant relationships among these variables in older adults (49-59 yr), possibly because of low reported levels of physical activity and TV. Multiple linear regression analysis revealed that physical activity and television watching in men and activity in women were significantly related to BMI. These data suggest that increasing activity levels and decreasing the time spent in sedentary behavior such as watching television should both be considered as potential intervention strategies in obesity prevention programs.

The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome.

Non-insulin-dependent diabetes mellitus (NIDDM) constitutes about 85% of all cases of diabetes in developed countries and it has now reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican- and African-Americans and Australian Aborigines and Torres Strait Islanders. The diagnosis of NIDDM is usually made after the age of 50 years in Europids, but it is seen at much younger age in these high prevalence populations, which also include Pacific Islanders, Native Americans, and migrant Asian Indians and Chinese. There is enormous variation in NIDDM prevalence between populations, and exceptionally high rates have been documented in populations who have changed from a traditional to a modern lifestyle, e.g., American Pima Indians, Micronesians, and other Pacific Islanders, Australian Aborigines, migrant Asian Indians, and Mexican-Americans. Over the next decade, following the initial phase of the NIDDM epidemic, macro- and microvascular complications will emerge as a major threat to future public health throughout the world with huge economic and social costs. The major cause of death in NIDDM is macrovascular disease (coronary artery, peripheral vascular, and cerebrovascular), which accounts for at least two-thirds of NIDDM mortality. A key strategy in reducing macrovascular disease lies in the better understanding of the Deadly Quartet or Metabolic Syndrome. New data suggest that hyperleptinemia rather than hyperinsulinemia may play an important and central role in the genesis of the cardiovascular disease risk factor cluster that constitutes the Metabolic Syndrome.

Is leptin sensitivity the link between smoking cessation and weight gain?

The known association between smoking cessation and weight gain, and the suggested role of leptin in the control of body weight, led to the present study which examined the association between smoking and serum leptin concentrations. Mean serum leptin levels, independent of body mass index (BMI), were calculated in male smokers and non-smokers from Nauru, Western Samoa and Mauritius. Smokers were generally leaner than non-smokers, and of similar ages. Levels of physical activity and glucose tolerance status were similar for smokers and non-smokers in Nauru and Western Samoa, while in Mauritius smokers were more active and less likely to be diabetic. Leptin concentrations in smokers were significantly lower than in non-smokers, even after adjusting for BMI, waist/hip ratio (WHR) or waist girth (P < or = 0.04). This association was independent of diabetes status. Smoking, via nicotinic mechanisms, may modify the sensitivity of hypothalamic leptin receptors and consequently modulate leptin synthesis and reduce body weight.

Parental hypertension and proteinuria in Pima Indians with NIDDM.

To determine if parental hypertension is associated with proteinuria in offspring with non-insulin-dependent diabetes mellitus (NIDDM), 438 diabetic Pima Indians (172 men, 266 women) aged 20 years or more and both of their parents were examined. Hypertension was defined as a systolic blood pressure 140 mm Hg or more, diastolic blood pressure 90 mm Hg or more, or treatment with antihypertensive medicine. Sixty-three percent of the fathers and 80% of the mothers had diabetes at the time their blood pressure was measured. Families in which either parent had proteinuria, defined as a urine protein-to-creatinine ratio > or = 0.5 g/g were excluded; 73 (16.7%) of the offspring had proteinuria. The prevalence rates of proteinuria in the offspring were similar if neither parent or only one parent had hypertension (8.9 and 9.4%, respectively), but was significantly higher if both parents had hypertension (18.8%), after adjustment for age, sex, duration of diabetes, and 2-h post-load plasma glucose concentration in the offspring and diabetes in the parents by logistic regression. The odds for proteinuria being present in the offspring if both parents had hypertension was 2.2 times (95% confidence interval, 1.2 to 4.2) that if only one parent had hypertension. When mean arterial pressure and blood pressure treatment in the offspring were added to the model the relationship remained (odds ratio = 2.2; 95% confidence interval, 1.1 to 4.3). Hypertension in both parents is associated with the development of proteinuria in offspring with NIDDM. This relationship was present even when controlled for the effects of blood pressure and its treatment in the offspring.

Hypertension in Pima Indians: prevalence and predictors.

THE PIMA INDIANS HAVE THE WORLD'S HIGHEST reported incidence of diabetes. Since 1965, this population has participated in a longitudinal epidemiological study of diabetes and its complications. The examinations have included a medical history for diabetes and other major health problems. The focus of this study is the correlation between the prevalence of hypertension and glucose tolerance in this population. Of the 4315 adults ages 18 and older, 50% had normal glucose tolerance; 12%, impaired glucose tolerance (IGT); 8%, newly diagnosed diabetes; and 31%, previously diagnosed diabetes of a mean duration of 11 years. Age-sex adjusted prevalence of hypertension was 24% in those with normal glucose tolerance, 34% in those with IGT, and 40% in those with diabetes. Hypertension was more common in men than in women and was positively related to obesity. Of the 2667 children ages 6 to 17 years, 4% had IGT, and 1% had diabetes. Blood pressure was higher in boys than girls and was associated with older age and worse glucose tolerance. Longitudinal analyses of data from 188 children ages 5 to 9 years who had their follow-up exam at ages 18 to 24 revealed no relationship between insulin concentration and blood pressure in either sex. In this group mean blood pressure at followup was positively correlated with relative weight, mean blood pressure, and 2-hour post-load plasma glucose concentration at baseline. In a multiple regression model, relative weight was the strongest predictor of mean blood pressure at the follow-up exam.