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Objective: Observational studies show breaking up prolonged sitting has beneficial associations with cardiometabolic risk markers, but intervention studies are required to investigate causality. We examined the acute effects on postprandial glucose and insulin levels of uninterrupted sitting compared with sitting interrupted by brief bouts of light- or moderate-intensity walking., Research Design and Methods: Overweight/obese adults (n = 19), aged 45-65 years, were recruited for a randomized three-period, three-treatment acute crossover trial: 1) uninterrupted sitting; 2) seated with 2-min bouts of light-intensity walking every 20 min; and 3) seated with 2-min bouts of moderate-intensity walking every 20 min. A standardized test drink was provided after an initial 2-h period of uninterrupted sitting. The positive incremental area under curves (iAUC) for glucose and insulin (mean [95% CI]) for the 5 h after the test drink (75 g glucose, 50 g fat) were calculated for the respective treatments., Results: The glucose iAUC (mmol/L) · h after both activity-break conditions was reduced (light: 5.2 [4.1-6.6]; moderate: 4.9 [3.8-6.1]; both P < 0.01) compared with uninterrupted sitting (6.9 [5.5-8.7]). Insulin iAUC (pmol/L) · h was also reduced with both activity-break conditions (light: 633.6 [552.4-727.1]; moderate: 637.6 [555.5-731.9], P < 0.0001) compared with uninterrupted sitting (828.6 [722.0-950.9])., Conclusions: Interrupting sitting time with short bouts of light- or moderate-intensity walking lowers postprandial glucose and insulin levels in overweight/obese adults. This may improve glucose metabolism and potentially be an important public health and clinical intervention strategy for reducing cardiovascular risk.

Background: Age is associated with both impaired glucose and insulin metabolism. To what extent the age-related changes in insulin resistance (IR) and beta-cell function contribute to the increase in prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) is less known, and this is investigated in this study., Methods: This study included 6610 men and 7664 women of different ethnic groups aged 30-69 years. IR and beta-cell function were examined by the homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-B). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression analysis adjusting for body mass index and study., Results: In Chinese men, the ORs (95% CIs) for IFG were 2.69 (1.70, 4.26), 2.51 (1.49, 4.21) and 2.89 (1.68, 4.97), respectively, in age groups of 40-49, 50-59 and 60-69 years compared with 30-39 years (p < 0.001 for trend); the corresponding figures for IGT were 1.73 (1.25, 2.38), 2.54 (1.78, 3.63) and 3.57 (2.46, 5.19) (p < 0.001 for trend). Similar trends for IGT were observed also in Chinese women and other ethnic groups, but not for IFG in Mauritius Indian and Creole men. Adjustment for HOMA-IR and HOMA-B reduced the ORs in all age groups of all ethnicities for both IFG and IGT, but the risk gradient between age groups remained particularly for the IGT., Conclusions: The age-related increase in glucose intolerance may not be fully explained by the defect in HOMA-IR and HOMA-B. As HOMA-IR and HOMA-B are only surrogate measures of insulin sensitivity and insulin secretion, the results need to be further investigated.

GHTD-amide is a tetrapeptide originally isolated from human urine that has hypoglycemic activity. Insulin occurs in secretory granules of beta cells as zinc-stabilized hexamers and must disperse to monomeric form in order to bind to its receptor. The aim of this study was to identify whether GHTD-amide and an analog called ISF402 (VHTD-amide) reduce blood glucose through enhancement of insulin activity by dispersing oligomers of insulin. Peptides containing the HTD-amide sequence and a free alpha-amino group were optimal at binding Zn(2+) and adopting secondary structure in the presence of Zn(2+). Binding was concentration dependent and resulted in a 1:1 Zn:peptide complex. In vitro the tetrapeptides dispersed hexameric insulin to dimers and monomers. GHTD-amide and ISF402 potentiated the activity of hexameric insulin when co-injected into insulin resistant Zucker rats. Injection of peptides with insulin caused reductions in blood glucose and C-peptide significantly larger than achieved with insulin alone, and serum insulin time profiles were also altered consistent with a reduced clearance or enhanced dispersal of the injected insulin. Insulin potentiation by ISF402 was reduced when lispro insulin, which does not form zinc-stabilized hexamers, was used in place of hexameric zinc insulin. In conclusion, GHTD-amide and ISF402 are zinc binding peptides that disperse hexameric insulin in vitro, and potentiate the activity of hexameric insulin more so than monomeric lispro insulin. These results suggest that dispersal of hexameric insulin through chelation of Zn(2+) contributes to the hypoglycemic activity of these tetrapeptides.

Inhibition of endosomal acidification disturbs insulin signaling in both liver and adipose cells. In this study we used MIN6 beta cells to determine whether bafilomycin, a potent inhibitor of the proton-translocating vacuolar ATPase, disrupts insulin signaling in islet beta cells. Pretreatment of MIN6 cells with varying concentrations of bafilomycin according to a time course revealed concentration and time-dependent changes in phosphorylation of insulin receptor signaling components. Increased phosphorylation of insulin receptor (IR), IRS2 and Akt was prolonged at low bafilomycin concentrations (10 and 50 nmol/L), whereas at high concentrations (100 and 200 nmol/L) phosphorylation rapidly returned to basal levels or below. Akt activation was demonstrated by transient increases in phosphorylation of BAD, cytoplasmic retention of FoxO1 and increased preproinsulin mRNA. Bcl2 expression was also transiently increased but reduced after 30 min exposure to bafilomycin, and this coincided with reduced cell viability. Thus, in beta cells inhibition of endosomal acidification by low concentrations of bafilomycin transiently increases insulin signaling, whereas high concentrations promote cell death. Bafilomycin and other agents that interfere with insulin signaling may contribute to diabetes development through disturbing homeostatic control of beta cell growth.

Aims: To compare diabetes management practices in 2001 among individuals from Tasmania, Australia, with a previous management survey conducted in 1995-7., Methods: Subjects were ascertained through the Tasmanian Insulin-Treated Diabetes Register. General demographic data were collected by telephone interview, and participants mailed a questionnaire on their diabetes management practices., Results: The response rate in 2001 was 80.8% (n=1336). There was a trend to more frequent blood glucose self-monitoring, notably in those less than 25 years (P<0.001 for monitoring >2 times/day), together with continued uptake of the pen system of insulin administration. More intensive shared management by general practitioner and diabetes specialist was noted, including a greater proportion visiting their doctor more than five times per year (P=0.006 for those <50 years). Most patients continue to be appropriately screened for hypertension and retinopathy. Dietitian visits declined overall (P=0.03 for at least annual visits), and there appeared to be an inadequate level of foot examination by patients and doctors., Conclusions: The survey indicated that most patients were taking greater responsibility for their metabolic control, and intensive management practices and more convenient methods of administration may be contributors. Two areas of possible concern are access to dietitian services, and patient and health provider education on appropriate foot care.

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.

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.

Longitudinal changes in serum insulin concentrations in relation to the natural history of glucose intolerance and factors associated with the incidence of NIDDM were studied in 838 nondiabetic Micronesian Nauruans over the 5.1-year period from 1982 to 1987. In 13 individuals who had data at three time-points and who developed NIDDM only at the final test, 2-h insulin levels followed an inverted V-shaped pattern as glucose tolerance declined to NIDDM. Subjects who were normal (n = 651) or had impaired glucose tolerance (IGT) (n = 187) at the 1982 baseline survey were divided into six natural history categories depending on glucose tolerance in 1987. Changes in glucose tolerance were accompanied by changes in mean 2-h insulin concentration that paralleled the inverted V pattern seen in the 13 individuals. Longitudinal changes in fasting insulin were less consistent, but mean levels increased as subjects developed NIDDM. The 5.1-year incidence of NIDDM was strongly related to baseline fasting and 2-h glucose concentrations, but associations with insulin levels were weak and inconsistent. Neither fasting nor 2-h insulin concentrations contributed to logistic regression models predicting deterioration in glucose tolerance, whereas fasting and 2-h glucose levels were included in all models and BMI also predicted deterioration from normal. These data showing sequential changes in insulin concentrations support the beta-cell exhaustion theory of NIDDM pathogenesis. However, in contrast to glucose concentrations and obesity, insulin levels are poor predictors of NIDDM risk in Nauruans. This reflects the complexity of interactions with other metabolic markers and the inability of a single examination to characterize the point along the inverted V curve of insulin secretion that an individual has reached.

Background: Asian Indians show an increased risk of non-insulin-dependent diabetes mellitus (NIDDM) and coronary heart disease, together with adverse fat distribution and hyperinsulinaemia relative to other ethnic groups. Using population-based data, we investigated the question of whether the adverse fat distribution observed in Indians can be explained by differences in behavioural risk factor levels. We have examined the question of whether ethnic differences in fat distribution are responsible for the unfavourable risk factor profile of Indians., Subjects and Methods: Fat distribution (waist: hip ratio) was compared in population-based samples of Asian Indian (n = 4394), Creole (n = 1746), and Chinese (n = 425) Mauritians, after controlling for body mass index and other factors. The contribution of this ratio to ethnic differences in cardiovascular disease risk factors and the role of fasting insulin concentrations were also determined., Results: Indian men had the highest mean waist: hip ratio, despite having the lowest body mass index. In Indian women the mean waist: hip ratio and body mass index were intermediate between those of Chinese and Creole women. Indians of both sexes had low levels of high-density lipoprotein (HDL) cholesterol and HDL: total cholesterol compared with Creoles or Chinese, whereas triglycerides levels were highest in Indian men but intermediate in Indian women. Mean fasting and 2 h insulin concentrations were not consistently highest in the Indian subgroups. Blood pressure and serum urate levels were lowest in Indians of both sexes and Indian women also had lower total cholesterol concentrations than either Creoles or Chinese. The elevated waist: hip ratio in Indians was not explained by differences in physical activity, cigarette smoking, or alcohol consumption and the differences in this ratio (and insulin levels) did not explain the observed ethnic differences in metabolic parameters., Conclusions: The susceptibility of Indians to abdominal obesity contributed to the less desirable levels of some, but not all, cardiovascular risk factors. Ethnic differences in cardiovascular risk factors in Mauritians were not explained by differences in abdominal obesity, serum insulin or behavioural risk factors. These data suggest that it is over-simplistic to ascribe the adverse cardiovascular risk factor profile commonly observed in Asian Indians to a tendency to abdominal obesity.

Total mortality and underlying cause of death were examined in a population-based prevalence cohort (n = 1232) of Tasmanians with insulin-treated diabetes mellitus. Eight and a half years after the establishment of the registry, the cause of death based on death certificate information was determined for the overall cohort and for three classification groups of insulin-treated diabetes: Group A--childhood-onset IDDM cases; Group B--adult-onset IDDM cases; and Group C--adult-onset insulin-treated NIDDM cases. A total of 378 deaths occurred, providing an overall SMR of 2.2 (95% CI 2.0-2.4) compared to the Tasmanian population. Diabetic females experienced a higher SMR (2.6, 95% CI 2.3-3.0) than diabetic males (1.9, 95% CI 1.6-2.2). The all-cause SMRs for the diabetic classification groups were 4.6 (95% CI 3.4-6.1) in Group A, 1.8 (95% CI 1.5-2.1) in Group B, and 2.2 (95% CI 1.9-2.6) in Group C. After adjusting for age, gender and duration of diabetes, the mortality in Group C was significantly higher compared to Group B (odds ratio 1.6, 95% CI 1.2-2.3). This study indicates that people with childhood-onset IDDM experience 4.6 times the death rate compared to the Tasmanian population and that the excess mortality is most pronounced in females.

Sera obtained at diagnosis from 273 children (0-14 years) with insulin-dependent diabetes mellitus (IDDM) were studied to compare different autoantibody levels. The subjects comprise 75% of all incident cases in New South Wales, Australia, for a 2-year period (ascertainment > 99% complete). Antibodies against glutamate decarboxylase were measured by radioimmunoprecipitation, insulin autoantibodies (on 176 sera collected within 4 days of initiation of insulin therapy) by radioimmunoassay, thyroid peroxidase and antigliadin IgA antibodies by enzyme-linked immunoassay, and anti-endomysial IgA and islet cell antibodies by indirect immunofluorescence. Reference ranges for anti-glutamate decarboxylase and insulin autoantibodies were determined in a group of non-diabetic children. Of the sera 69% were positive for anti-glutamate decarboxylase, 65% for insulin autoantibodies, 71% for islet cell antibodies (> or = 20 Juvenile Diabetes Foundation units), 10% for anti-thyroid peroxidase, 2.6% for antigliadin and 3.0% for anti-endomysial antibodies. Islet cell antibodies and insulin autoantibodies were both negative in 13.7% of the sera, while only 5.8% were negative for all three of islet cell antibodies, insulin autoantibodies and anti-glutamate decarboxylase. There was a higher frequency of anti-glutamate decarboxylase among girls than boys (75% vs 63%, p = 0.03) and a negative correlation between the level of insulin autoantibodies and age at diagnosis (r = -0.41, p < 0.0001). A higher frequency of antithyroid peroxidase was found with increasing age (p = 0.05). Higher titres of islet cell antibodies were associated with a higher frequency of both anti-glutamate decarboxylase (p < 0.0001) and insulin autoantibodies (p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Type 1 diabetes mellitus in adults may present in a manner similar to that of Type 2 diabetes but with a late development of insulin dependency. We studied 65 patients who presented with 'adult-onset' diabetes after the age of 30 years. Of these patients, 19 required insulin therapy. The insulin-treated patients were significantly younger, their onset of diabetes was at an earlier age, and their postprandial serum C-peptide levels were lower than those of the non-insulin-treated group. Moreover, the insulin-treated subjects had a higher mean concentration of antibodies to glutamic acid decarboxylase (GAD) (66.8 +/- 10.2 units) than the patients who did not require insulin (9.9 +/- 1.9 units) (p < 0.001) and their frequency of anti-GAD positivity was 73.7% versus 4.3% (p < 0.001). Thus, among patients attending a diabetes clinic, the majority (73.7%) of subjects who presented with diabetes after 30 years of age and who subsequently required therapy with insulin, actually have the islet cell lesion of Type 1 diabetes which progresses at a slower tempo than in children. We conclude that testing for anti-GAD in adult-onset non-obese diabetic patients should be a routine procedure in order to detect latent insulin-dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.

Cross-sectional associations between insulin and ECG abnormalities suggestive of 'possible' and 'probable' coronary heart disease (CHD) in the populations of Nauru (n = 568) and Mauritius (n = 3280) have been examined in both non-diabetic and diabetic subjects. Additionally, the longitudinal relationship between baseline insulin and incident ECG abnormalities has been explored in non-diabetic Nauruans (n = 177) over 5 years. Age-adjusted mean 2-hour serum insulin was generally higher in subjects with ECG abnormalities than those with a normal ECG, but the difference was significant only for non-diabetic Mauritian men (p < 0.01). There was no clear association between prevalence of ECG abnormalities and quintiles of fasting or 2-hr insulin in Mauritians, and in non-diabetic Nauruans there was a non-significant positive association between prevalence of ECG abnormalities and tertiles of 2-hr insulin. Logistic regression analyses showed a slight positive association between 2-hr insulin and ECG abnormalities in non-diabetic Mauritians (p = 0.06 in males, p = 0.09 in females), and non-diabetic male Nauruans (p = 0.054) independent of possible confounders. Fasting insulin was not associated in any group. In longitudinal analyses in Nauruans there were no significant differences in mean baseline fasting or 2-hr serum insulin between subjects who maintained a normal ECG and those who developed abnormalities consistent with 'possible CHD' (there were no changes suggestive of 'probable CHD'). The incidence of ECG changes suggesting 'possible CHD' was slightly higher in the upper tertile of baseline fasting insulin in both sexes and 2-hr insulin in females, but when other factors were accounted for, multiple logistic regression analyses did not support this finding. Data from the populations of Mauritius and Nauru do not support a major role for serum insulin in ECG abnormalities suggestive of CHD.

The relationship of 2-hour (post-75 g oral glucose) serum insulin levels with plasma glucose levels was studied in a population-based random sample comprising 2,627 Hindu Indians, 685 Muslim Indians, 1,351 Creoles (African, European, and Indian admixture), and 415 Chinese from the Indian Ocean island of Mauritius. Known diabetic subjects taking oral hypoglycemic drugs or insulin were excluded from these analyses; 64% of all diabetic subjects had usable glucose and insulin data. Both fasting and 2-hour postload insulin levels were significantly higher in women than in men, and levels in both sexes were significantly greater in Hindu and Muslim Indian subjects than in Creoles or Chinese even after controlling for differences in age, body mass index (BMI), waist to hip ratio (WHR), and plasma glucose level. Levels in Muslims were higher than those in Hindus; it was unclear whether these ethnic differences represented hereditary or unmeasured environmental factors closely associated with ethnicity. All four ethnic groups demonstrated similar inverted U- or V-shaped curves when 2-hour insulin was plotted against either basal or 2-hour glucose. Both quadratic (U) and two-piece (V) regression models improved over linear models for 2-hour insulin versus either fasting or 2-hour glucose in all ethnic groups, although in statistical terms they were good models only for the 2-hour glucose comparison. The two-piece models were associated with modest increases in R2 compared with the quadratic models, but it was not possible to precisely determine optimal turning points with either model. However, in all ethnic groups, 2-hour insulin levels decreased above glucose levels of 7.1 to 7.8 (fasting) and 11.3 to 13.5 mmol/L (2-hour) in quadratic models, and 7.5 to 9.5 (fasting) and 8.5 to 10.5 mmol/L (2-hour) in two-piece models. The shape and point of inflection of the quadratic and two-piece curves were influenced little by gender, obesity, fat distribution, and physical activity. These results are in accord with those observed in cross-sectional and longitudinal studies in other ethnic groups, and support the generality of the plasma glucose levels currently used to define diabetes mellitus, which physiologically correspond with a decrease in beta-cell responsiveness to glucose. Asian Indians appear to have an ethnic propensity to hyperinsulinemia that is not explained by obesity or adverse fat distribution.

Objectives: There is conflicting evidence of a link between circulating insulin concentrations and blood pressure. The aim of this study, therefore, was to investigate this relationship in a representative population sample of different ethnic groups., Design: A cross-sectional study was performed, using a random cluster sample of 5080 adults aged 25-74 years from the Indian Ocean island of Mauritius., Methods: Glucose tolerance was assessed with a 75-g oral glucose tolerance test. Hypertension and glucose tolerance were classified using World Health Organization criteria. Subjects known to have diabetes before the survey were excluded from these analyses, leaving 3104 Asian Indian, 1256 African-origin Creole and 384 Chinese subjects eligible for this study., Results: There were statistically significant linear correlations between fasting and 2-h insulin and mean blood pressure in all sex-ethnic subgroups, except for Chinese men. However, after controlling for age and the body mass index, partial correlations were much reduced and remained significant only for fasting insulin in Indian men (r = 0.07, P < 0.01) and women (r = 0.09, P < 0.001) and 2-h insulin in Chinese women (r = 0.15, P < 0.05). After controlling for age and body mass index, mean fasting and 2-h insulin concentrations were not significantly different between hypertensive and normotensive subjects in any of 36 possible subgroups defined by ethnic group, gender or glucose tolerance (normal, impaired glucose tolerance or newly diagnosed diabetes). In both men and women with normal glucose tolerance (ethnic groups combined) there was no evidence of increasing systolic or diastolic blood pressure across quartiles of either fasting or 2-h serum insulin within any quartile of the body mass index. By contrast, at any given level of serum insulin there was a clear association between an increasing body mass index and increasing blood pressure, suggesting strongly that insulin is not the final pathway by which obesity influences blood pressure., Conclusions: This study of three ethnic groups does not support the hypothesis that the circulating insulin concentration is an independent determinant of blood pressure in populations.

This study aimed to compare plasma insulin concentrations across the age-range from childhood to old age in the populations of Nauru and Tuvalu, and to assess their relationship to the incidence of impaired glucose tolerance and diabetes in young Nauruans. The studies, performed in 1975 and 1976, found that Nauru had a higher prevalence of Type 2 (non-insulin-dependent) diabetes mellitus than Tuvalu. Both studies included subjects of 8-29 years of age (n = 320 in Nauru, n = 318 in Tuvalu) and on these subjects glucose tolerance status, body mass index and fasting and 2-h (post 75 g glucose load) plasma insulin concentrations were determined. In Nauru, follow-up surveys in 1982 and 1987 included many of the subjects first seen in 1975/1976, allowing the incidence and natural history of glucose intolerance to be studied. Within the group of subjects with normal glucose tolerance, there was no effect of age on plasma insulin distributions in either population. However, in both populations, 8-19 year old subjects with normal glucose tolerance had higher body mass index-adjusted geometric mean fasting and 2-h insulin concentrations than older age-groups (p less than 0.001 for fasting insulin). Body mass index-adjusted geometric mean 2-h plasma insulin was higher in subjects with abnormal glucose tolerance relative to those with normal glucose tolerance in both populations. In Nauruans, 2-h insulin levels at baseline were predictive of impaired glucose tolerance and Type 2 diabetes in 1982, and fasting and 2-h insulin levels predicted development of Type 2 diabetes in 1987.(ABSTRACT TRUNCATED AT 250 WORDS)

The evidence linking insulin to blood pressure is controversial, and results for groups similarly categorized by body mass, glucose tolerance and hypertensive status are often contradictory. We have investigated the relationship in three population-based samples of Micronesian (Nauru), Polynesian (Western Samoa) and Melanesian (New Caledonia) Pacific islanders, who are known to be susceptible to obesity, non-insulin-dependent diabetes mellitus (NIDDM), hyperinsulinaemia and hypertension. After controlling for age and body mass index (BMI), mean fasting and 2-hr (post 75 g glucose) insulin levels were not significantly different between hypertensive and non-hypertensive subjects, in any population or glucose tolerance sub-group, excepting 2-hr insulin in New Caledonians with normal glucose tolerance. Similarly, there were no strong trends for a higher prevalence of hypertension amongst those with insulin levels in the upper quartile of the distribution of each population, although it was apparent in some BMI/glucose tolerance sub-groups of two populations. Multiple linear regression analyses also showed an inconsistent and where present, weak, independent association between insulin and blood pressure in models predicting both systolic and diastolic blood pressure. We therefore conclude that the hypothesis implicating insulin as a major determinant of blood pressure and as the pathophysiological link between obesity, NIDDM and hypertension is not strongly supported either by the literature or the present data.

The effect of continuous subcutaneous insulin infusion (CSII) on glycaemic control and insulin binding to erythrocytes was studied in six diabetic patients. A marked improvement in blood glucose control during CSII was observed in these patients previously on conventional therapy. Specific 125I-insulin binding to erythrocytes of the diabetics before the institution of CSII was significantly lower than that of age-, weight- and sex-matched nondiabetic subjects, 6.5 +/- 0.1% vs. 9.8 +/- 0.3% (P less than 0.05). After 4-6 months of CSII, insulin binding was restored to normal levels. This normalization in insulin binding to erythrocytes of patients on CSII was due to a 35% increase in active binding sites, together with a small change in binding affinity.

A longitudinal study of 266 randomly selected nondiabetic Nauruans [215 with normal tolerance and 51 with impaired glucose tolerance (IGT)] over 6 yr showed that deterioration in glucose tolerance status had occurred in 61 subjects. Of the subjects with initially normal tolerance, 34 (16%) progressed to IGT and 14 (6.5%) progressed to diabetes. Thirteen of the subjects with IGT (25%) progressed to diabetes. Subjects were examined in 1975 through 1976, and follow-up examinations were performed in 1982. After age, a high 2-h plasma insulin response to a glucose load was the factor most predictive of progression from normal tolerance to both diabetes (P less than .001) and IGT (P less than .01). Both a high 2-h glucose level and greater obesity independently predicted progression from IGT, and a diminished 2-h insulin response just failed to significantly improve the model (P less than .06). The negative parameter of the insulin response associated with deterioration from IGT differed significantly (P less than .01) from the positive-parameter estimate of the response associated with progression to diabetes from normal tolerance (P less than .01), implying a qualitative difference between these nondiabetic subgroups. The use of a glucose-insulin interaction term to predict progression to diabetes for all nondiabetic subjects confirmed this difference; this term's addition improved the model (P less than .01), and progression to diabetes was associated with a high insulin response for 2-h glucose less than 7.8 mM but a low response for 2-h glucose greater than 7.8 mM.

Oral glucose tolerance tests were performed in the morning and afternoon of separate days on 31 people derived from a normal population sample. Blood sugar levels were higher in the afternoon test from and including 60 minutes after the glucose load. The degree of diurnal variation was similar in men and women, but greater in the older half of the group. It was negatively correlated with the degree of obesity. The plasma insulin response was less at the 30 minute time point in the afternoon, but significantly exceeded the morning values at 120 and 150 minutes after the glucose load. Growth hormone levels were similar in morning and afternoon tests. Fasting non-esterified fatty acid levels were significantly higher before the afternoon test.The relatively impaired glucose tolerance in the afternoon is associated with a delayed insulin response to the glucose load. This seems unlikely to be the sole explanation, however, and increased non-esterified fatty acid metabolism with a consequent decrease in glucose disposal may also contribute.