Prevalence and incidence of NIDDM in Daqing City

OBJECTIVE: To investigate the prevalence and incidence of non-insulin dependent diabetes (NIDDM) in China by WHO criteria. METHODS: In the prevalence survey of NIDDM all 110660 participants (55391 men, 53269 women) were inhabitants of Daqing City, the largest oil center in northeast China, accounting for 87.3% of the 25 to 74 aged population in this city. They were screened by measuring two-hour plasma glucose concentrations (PG2 h) after a breakfast containing at least 80 g of carbohydrate, then a standard oral glucose tolerance test (OGTT, 75 g glucose load) was performed in 4209 subjects with PG2 h more than 6.67 mmol/L in this screen. NIDDM and impaired glucose tolerance (IGT) were diagnosed using WHO criteria. Incidence survey was made in 36471 non-diabetics identified in the prevalence survey. Two-hour urine-glucose after breakfast was determined during first screen. The urine-glucose trace or positive subjects were then followed by OGTT. Glucose was measured by glucose oxidation method. RESULTS AND CONCLUSIONS: In prevalence survey, 630 newly diagnosed NIDDM (296 males, 334 females) and 596 IGT (318 males, 278 females) were found in 110660 (male:female = 55391/53269) studied subjects in addition to 190 previously diagnosed NIDDM. Thus the total prevalence of NIDDM was 7.7/1000, and IGT was 5.5/1000. Standardized to the Chinese population in 1982, the prevalences are 12.6/1000 (95% CI = 12.0/1000-13.3/1000) and 7.7/1000 (95% CI = 7.16/1000-8.19/1000) respectively. In the incidence survey, 191 NIDDM (103 males, 88 females) were diagnosed in the 36471 (male:female = 18801/17670) non-diabetics from 1986 to 1990, thus the annual incidence of NIDDM was 131/100000 (137 males, 125 females). Standardized incidence is 131/100000 (95% CI = 94/100000-168/ 100000). It is estimated that there would be more than 700 thousand new diabetics per year in 24-74 years old Chinese if Chinese population were 1.3 billion in the early 21st century.     

The effect of noninsulin dependent diabetes mellitus on the prevalence of clinical osteoarthritis. A population based study

OBJECTIVE: To explore the relation between noninsulin dependent diabetes mellitus (NIDDM) and osteoarthritis (OA) in a population. METHODS: The study population included 632 men and 882 women aged 52-95 years from the Rancho Bernardo community. In 1984-87, participants answered questions about history of diabetes and had a standard oral glucose tolerance (OGTT). In 1988-92, subjects completed a questionnaire about history of arthritis, type of arthritis diagnosed, and presence of joint pain. Nurses examined subjects for presence of Heberden's nodes. Subjects with no history of arthritis were compared to those with a history of OA and other types of arthritis with regard to age, body size, and plasma glucose levels. In addition, subjects were classified by diabetes status to determine differences in the prevalence of arthritis and related characteristics. RESULTS: Neither impaired glucose tolerance nor NIDDM was associated with history of OA, regardless of how inclusive the definition of OA, before or after adjustment for age and maximum lifetime obesity. In age and obesity adjusted analyses, men with a history of OA had lower fasting plasma glucose levels than men with no arthritis (100.2 vs. 103.6 mg/dl, p < 0.05), and men with NIDDM had less hand and hip pain than normoglycemic men (p < 0.05). Heberden's nodes were unrelated to glucose tolerance status. CONCLUSION: This population based study found no positive association between clinical OA and NIDDM defined by OGTT. These results are compatible with community based data examining radiographic OA and history of diabetes.     

Risk factors for the development of NIDDM in Yonchon County, Korea

OBJECTIVE: To determine the risk factors for the development of NIDDM in Yonchon County of Korea. RESEARCH DESIGN AND METHODS: We studied 1,193 Korean nondiabetic subjects at baseline who participated in a 2-year follow-up study on diabetes in Yonchon County. A 75-g oral glucose tolerance test was performed 2 years after the baseline examination. Age, sex, and anthropometric and metabolic characteristics at baseline were analyzed simultaneously as potential predictors of conversion to NIDDM. We also designed a nested case-control study to determine the role of hyperinsulinemia and/or hyperproinsulinemia in the conversion to NIDDM in patients with newly developed diabetes and control subjects matched for age, sex, BMI, and waist-to-hip-ratio. RESULTS: At 2 years, 67 subjects developed diabetes, as defined by World Health Organization criteria. The age-adjusted incidence was significantly higher in men (6.4%) than in women (3.0%), and the incidence increased as age increased in both sexes. Multiple logistic regression analysis revealed age, male sex, and fasting and 2-h glucose levels to be significant risk factors for the development of NIDDM, whereas waist-to-hip ratio and BMI were not. In a nested case-control study, baseline proinsulin but not insulin levels were significantly higher in subjects who progressed to NIDDM than in those who did not. CONCLUSIONS: In the Korean population, beta-cell dysfunction, as measured by high proinsulin levels, seems to be associated with subsequent development of NIDDM, whereas regional and general obesity and fasting insulin levels, which may be a surrogate for insulin resistance, were not.     

The distribution of cartilage degeneration of the human patella in relation to individual subchondral mineralization

OBJECTIVE--To evaluate androgen concentrations in relation to insulin resistance in men and women with and without NIDDM. Recent studies have indicated the potential importance of the regulation of insulin sensitivity by androgens in both women and men. Low sex hormone binding globulin (SHBG) concentration is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM) in women and is strongly associated statistically with signs of insulin resistance. RESEARCH DESIGN AND METHODS--We compared measurements of anthropometric variables and SHBG, steroid hormone, and insulin concentrations of women and men who have NIDDM with those of control subjects. RESULTS--Women with NIDDM had somewhat higher plasma insulin concentrations, lower SHBG, and higher free testosterone values than did control subjects with similar body mass index (BMI). Women with NIDDM had marginally higher waist-to-hip ratios (WHR). Plasma insulin concentrations correlated positively with BMI, WHR, and free testosterone and negatively with SHBG. In multivariate analyses, insulin concentrations remained positively associated with BMI and free testosterone. Men with NIDDM had higher fasting plasma insulin concentrations than did the nondiabetic control subjects. Testosterone and SHBG were lower in the diabetic men than in both control groups. The derived value of free testosterone was not different between groups. Univariate correlation analyses revealed tight statistical couplings between plasma insulin on the one hand and SHBG and testosterone concentrations (negative) on the other. In multivariate analyses, only the insulin-testosterone association remained. CONCLUSIONS: Women with NIDDM have high levels of free testosterone and low levels of SHBG. Insulin resistance is closely correlated with these signs of hyperandrogenicity as well as with obesity. Men with NIDDM also have low levels of SHBG and, in contrast to women, low testosterone values. Insulin values correlate negatively with these hormonal factors. Based on the results of experimental work and intervention studies, we suggest that these androgen abnormalities might be causally related to insulin resistance in NIDDM.     

Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study

Obesity is an established risk factor for non-insulin-dependent diabetes mellitus (NIDDM). Anthropometric measures of overall and central obesity as predictors of NIDDM risk have not been as well studied, especially in women. Among 43,581 women enrolled in the Nurses' Health Study who in 1986 provided waist, hip, and weight information and who were initially free from diabetes and other major chronic diseases, NIDDM incidence was followed from 1986 to 1994. After adjustment for age, family history of diabetes, smoking, exercise, and several dietary factors, the relative risk of NIDDM for the 90th percentile of body mass index (BMI) (weight (kg)/height (m)2) (BMI = 29.9) versus the 10th percentile (BMI = 20.1) was 11.2 (95% confidence interval (CI) 7.9-15.9). Controlling for BMI and other potentially confounding factors, the relative risk for the 90th percentile of waist: hip ratio (WHR) (WHR = 0.86) versus the 10th percentile (WHR = 0.70) was 3.1 (95% CI 2.3-4.1), and the relative risk for the 90th percentile of waist circumference (36.2 inches or 92 cm) versus the 10th percentile (26.2 inches or 67 cm) was 5.1 (95% CI 2.9-8.9). BMI, WHR, and waist circumference are powerful independent predictors of NIDDM in US women. Measurement of BMI and waist circumference (with or without hip circumference) are potentially useful tools for clinicians in counseling patients regarding NIDDM risk and risk reduction.     

Defects in insulin secretion and action in women with a history of gestational diabetes

Gestational diabetes mellitus (GDM) is associated with defects in insulin secretion and insulin action, and women with a history of GDM carry a high risk for the development of non-insulin-dependent diabetes mellitus (NIDDM). Assessment of subjects with a history of GDM who are currently normoglycemic should help elucidate some of the underlying defects in insulin secretion or action in the evolution of NIDDM. We have studied 14 women with normal oral glucose tolerance who had a history of GDM. They were compared with a group of control subjects who were matched for both body mass index (BMI) and waist-to-hip ratio (WHR). All subjects underwent tests for the determination of oral glucose tolerance, ultradian oscillations in insulin secretion during a 28-h glucose infusion, insulin secretion in response to intravenous glucose, glucose disappearance after intravenous glucose (Kg), and insulin sensitivity (SI) as measured by the Bergman minimal model method. The BMI in the post-GDM women was similar to that in the control subjects (24.9 +/- 1.2 vs. 25.4 +/- 1.4 kg/m2, respectively), as was the WHR ratio (0.80 +/- 0.01 vs. 0.76 +/- 0.01, respectively). The post-GDM women were slightly older (35.2 +/- 0.9 vs. 32.1 +/- 1.4 years, P = 0.04). The fasting plasma glucose levels were significantly higher in the post-GDM group than in the control group (4.9 +/- 0.1 vs. 4.4 +/- 0.1 mmol/l, respectively, P < 0.001) and remained higher at each of the subsequent determinations during the oral glucose tolerance test, although none had a result indicative of either diabetes or impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic beta-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothesized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 +/- 3.1 and 24.2 +/- 2.2 for the lean controls, 52 +/- 2.5 and 28.7 +/- 0.9 for the NIDDM subjects and 60 +/- 2 and 27.6 +/- 2.1 for the obese, non-diabetic subjects (mean +/- S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme. A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91 +/- 11, 96 +/- 3 and 146 +/- 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 +/- 0.92, 10.83 +/- 2.03 and 14.68 +/- 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 +/- 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 +/- 7, 164 +/- 7 and 179 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 +/- 7, 87 +/- 6 and 86 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome: hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.     

Evidence that plasma leptin and insulin levels are associated with body adiposity via different mechanisms

OBJECTIVE: Like insulin, the adipocyte hormone, leptin, circulates at levels proportionate to body adiposity. Because insulin may regulate leptin secretion, we sought to determine if plasma leptin levels are coupled to body adiposity via changes in circulating insulin levels or insulin sensitivity and whether leptin secretion from adipocytes is impaired in subjects with NIDDM. RESEARCH DESIGN AND METHODS: We used multiple linear regression to analyze relationships between BMI (a measure of body adiposity) and fasting plasma levels of leptin and insulin in 98 nondiabetic human subjects (68 men/30 women) and 38 subjects with NIDDM (27 men/11 women). The insulin sensitivity index (Si) was also determined in a subset of nondiabetic subjects (n = 38). RESULTS: Fasting plasma leptin concentrations were correlated to both BMI (r = 0.66, P = 0.0001) and fasting plasma insulin levels (r = 0.65, P = 0.0001) in nondiabetic men and women (r = 0.58, P = 0.0009 for BMI; r = 0.47, P = 0.01 for insulin). While the plasma leptin level was also inversely related to Si (r = -0.35; P = 0.03), this association was dependent on BMI, whereas the association between insulin and Si was not. Conversely, the relationship between plasma leptin and BMI was independent of Si, whereas that between insulin and BMI was dependent on Si. The relationship between plasma leptin levels and BMI did not differ significantly among NIDDM subjects from that observed in nondiabetic subjects. CONCLUSIONS: We conclude that 1) body adiposity, sex, and the fasting insulin level are independently associated with plasma leptin level; 2) because NIDDM does not influence leptin levels, obesity associated with NIDDM is unlikely to result from impaired leptin secretion; and 3) insulin sensitivity contributes to the association between body adiposity and plasma levels of insulin, but not leptin. The mechanisms underlying the association between body adiposity and circulating levels of these two hormones, therefore, appear to be different.     

Chemical respiratory allergy, IgE and the relevance of predictive test methods: a commentary

Polycystic ovary syndrome is a diagnosis made in 5%-10% of women between late adolescence and the menopause. Patients may present with oligomenorrhoea or amenorrhoea, anovulation or infertility, hirsutism or acne. Women with the syndrome have at least seven times the risk of myocardial infarction and ischaemic heart disease of other women, and by the age of 40 years up to 40% will have type 2 diabetes or impaired glucose tolerance. Polycystic ovary syndrome is associated with insulin resistance, with consequent hyperinsulinaemia and (frequently) hyperlipidaemia and obesity. Recent research has shown that the application of diabetes management techniques aimed at reducing insulin resistance and hyperinsulinaemia (such as weight reduction and the administration of oral hypoglycaemic agents) can not only reverse testosterone and luteinising hormone abnormalities and infertility, but can also improve glucose, insulin and lipid profiles. The management of polycystic ovary syndrome should now include patient education and attention to diabetes and cardiovascular risk factors such as hyperlipidaemia, obesity, physical exercise, glucose intolerance, hypertension and cigarette smoking.     

A new spontaneous animal model of NIDDM without obesity in the musk shrew

The EDS (early-onset diabetes in suncus) colony has been developed as a new closed breeding colony of the musk shrew (Suncus murinus, Insectivora) exhibiting a high incidence of spontaneous diabetes mellitus. We investigated the characteristic features of diabetic shrews in this colony. All diabetic shrews are characterized by glycosuria (Tes-tape value > or = 3+), hyperglycemia (23.3 +/- 0.8 mmol/l) and polyuria, and they were affected by the age of 3 months. Cumulative incidence (64.1% in males and 27.8% in females) was kept intact after the age of 3 months. The growth pattern of diabetic shrews was similar to that of non-diabetic shrews, and obesity was not consistent in diabetic shrews. The intraperioneal glucose tolerance test revealed both impaired glucose tolerance and impaired insulin secretion in diabetic shrews. Insulin sensitivity of diabetic shrews decreased in the intraperioneal insulin tolerance test. Neither severe hypertrophy nor lymphocytic infiltration was observed in pancreatic islets of diabetic shrews. These facts suggested that diabetic shrews in the EDS colony should be classified as early-onset non-insulin dependent diabetes mellitus (NIDDM) without obesity. Early-onset of severe hyperglycemia with impaired glucose tolerance is a distinctive character compared with other non-obese NIDDM models in rodents. We concluded that the diabetic shrews in the EDS colony are a new animal model of human NIDDM without obesity.     

Perinatal mortality and its relationship to the reporting of low-birthweight infants

OBJECTIVE: To determine whether diabetes defined by isolated postchallenge hyperglycemia (IPH) (2-h postchallenge plasma glucose > or = 11.1 mmol/l with fasting plasma glucose [FPG] < 7.0 mmol/l) increases the risk of fatal cardiovascular disease (CVD) in older women and men. RESEARCH DESIGN AND METHODS: In a prospective study, we followed 769 men and 1,089 women, aged 50-89 years, who had no history of diabetes or myocardial infarction and demonstrated no fasting hyperglycemia (i.e., FPG < 7.0 mmol/l) when they underwent oral glucose tolerance testing at baseline in 1984-1987. RESULTS: At baseline, 70% of 125 women and 48% of 133 men with previously undiagnosed diabetes had IPH. Over the next 7 years, women with IPH had a significantly increased risk of fatal CVD and heart disease compared with nondiabetic women. This increased risk was not observed in men with IPH. This association was independent of age, hypertension, central obesity, cigarette smoking, HDL cholesterol, and triglycerides (multiply adjusted hazard ratio and 95% CI: 2.6 and 1.4-4.7 for CVD; 2.9 and 1.3-6.4 for heart disease). CONCLUSIONS: Diabetes defined by IPH alone is common in older adults and more than doubles the risk of fatal CVD and heart disease in older women. Because the prevalence of IPH increases with age, the use of fasting glucose alone for diabetes screening or diagnosis may fail to identify most older adults at high risk for CVD and should be reevaluated.     

Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction

Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.     

Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)

The diagnostic criteria of the US National Diabetes Data Group and the World Health Organization have stimulated a major increase throughout the world in epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). They have established that much of NIDDM is undiagnosed, that onset of NIDDM occurs at least 7 y before its diagnosis, and that significant morbidity and premature mortality occur in subjects with undiagnosed diabetes. New studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of NIDDM as they move to urban or nontraditional situations, often with 5- to 10-fold increases in NIDDM prevalence. Epidemiologic studies have documented that major risk factors for NIDDM include increasing age, greater obesity, longer duration of obesity, unfavourable body fat distribution, physical inactivity, and hyperinsulinemia. All these factors interact with unknown genetic factors to produce NIDDM. Studies have shown that genes for diabetes, as yet undetermined, are a necessary cause of NIDDM. Hyperinsulinemia exists in childhood in populations at high risk for NIDDM. Stimulated by obesity, upper body obesity, and physical inactivity, insulin resistance develops, accompanied by impaired glucose tolerance. The pressure of the NIDDM risk factors continues this process of insulin resistance/hyperinsulinemia/hyperglycemia, until glucose toxicity to the beta cell results in inability to secrete sufficient insulin, resulting in decompensated fasting hyperglycemia.     

Cardiovascular risk factors prior to the development of non-insulin-dependent diabetes mellitus in persons with impaired glucose tolerance: the Hoorn Study

The aim of the study was to analyze cardiovascular risk factors as predictors for developing non-insulin-dependent diabetes mellitus (NIDDM) in people with impaired glucose tolerance. A cross-sectional survey of glucose tolerance was conducted in people, aged 50-74, who were randomly selected from the registry of the middle-sized town Hoorn (The Netherlands). Based on the mean values of two oral glucose tolerance tests, people were classified in glucose tolerance categories according to the WHO criteria. The mean follow-up time was 36 months (range 13-55 months). The cumulative incidence of NIDDM was 34% (95% CI 16.9-45.1). In multiple logistic regression analysis, cardiovascular risk factors at baseline did not predict the conversion from impaired glucose tolerance to NIDDM, in contrast with the two-hour plasma glucose level (odds ratio 3.56, p < 0.001) and the fasting proinsulin level, as one of the determinants of beta-cell dysfunction (Odds ratio 2.1, p < 0.05). The baseline HDL-cholesterol level, one of the components of the insulin resistance syndrome, was associated with the conversion from impaired glucose tolerance to normal glucose tolerance (Odds ratio 1.58, p < 0.05). The results of our study seem to support the hypothesis that conversion from impaired glucose tolerance to normal glucose tolerance depends on insulin resistance and the development of NIDDM from impaired glucose tolerance depends on beta-cell dysfunction.     

Gestational diabetes mellitus and subsequent development of overt diabetes mellitus

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.     

Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.     

Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat

OBJECTIVE: Non-insulin-dependent diabetes mellitus (NIDDM) is often associated with hypertension leading to a specifically high cardiovascular risk in these patients. However, there is evidence that insulin resistance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertriglyceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resistance have been suggested to be of major pathophysiological importance for the development of this syndrome (syndrome X). Since imidazoline receptors are currently considered to be a specific pharmacological target for blood pressure reduction, it is important to know whether and in which way these compounds affect the glucose homoeostasis and insulin release. DESIGN: The influence of moxonidine on glucose tolerance in vivo was determined in healthy control rats, in rats receiving a high fructose diet for 6 weeks to induce insulin resistance, hyperinsulinaemia and hypertension, and in rats receiving in addition to a high fructose diet moxonidine (1.5 mg/kg body weight daily). In vitro, using isolated pancreatic islets of mice, long-lasting effects (chronic) and immediate (acute) effects of moxonidine on beta-cell function were determined by basal and glucose stimulated insulin release in two different experimental systems: (1) islets were exposed for 24 h (37 degrees C) to various concentrations of moxonidine ranging from 1 nmol/l to 1 mmol/l, followed by a washing procedure to remove excess of moxonidine and then used for the beta-cell function test; (2) islet cultures were incubated again with moxonidine for 24 h (37 degrees C) with either 1 nmol/l or 1 micromol/l. In contrast to the first experiments, however, after the washing procedure moxonidine was added at the same concentration as used for preincubation to test its direct effect on beta-cell function. RESULTS: In healthy control rats acute administration of moxonidine in vivo impaired the glucose tolerance in high dosages, which effectively reduced the blood pressure (>1 mg/kg body weight). This effect was, however, smaller that that observed by clonidine. In fructose-fed rats, moxonidine completely prevented the development of insulin resistance, hyperinsulinaemia and hypertension. In vitro, pancreatic islets preincubated with moxonidine exhibited dose-dependently both stimulatory and inhibitory chronic effects on beta-cell function compared with that in controls. Preincubation of islet cultures with moxonidine at concentrations between 1 nmol/l and 1 mmol/l resulted in a reduction of basal insulin release which was very pronounced at concentrations higher than 100 nmol/l. The results obtained for glucose-stimulated insulin release opposed in part those for basal insulin release, since the preincubation with moxonidine up to 10 micromol/l gave rise to an increased insulin release. An additional direct effect of moxonidine with a marked reduction of glucose-stimulated insulin release was observed, however, when moxonidine was present during the preincubation (24 h) and the functional test at a concentration of 1 nmol/l or 1 micromol/l. CONCLUSIONS: Our data suggest that a causal linkage exist between the development of hypertension and insulin resistance/hyperinsulinaemia in the high fructose diet rat model. Since central activation of imidazoline receptors by moxonidine can prevent this syndrome, it follows that an overactivity of the sympathetic nervous system is of major importance. Suppression of this sympathetic overactivity might be an effective approach to reduce hypertension and the concomitant metabolic defect. Therefore, such an interventional strategy could contribute to reduce the cardiovascular risk of NIDDM patients and patients with other forms of insulin resistance/hyperinsulinaemia such as metabolic cardiovascular syndrome.     

Chiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeys

Previously, we demonstrated that nondiabetic insulin-resistant monkeys had reduced covalent insulin activation of muscle glycogen synthase (GS) compared to normal monkeys and that covalent insulin activation of adipose tissue GS was absent in these monkeys. Covalent insulin activation of muscle and adipose tissue GS in monkeys with impaired glucose tolerance and noninsulin-dependent diabetes (NIDDM) was also absent. As in humans, monkeys with NIDDM have a lower urinary excretion rate of chiroinositol (CI), a component of a putative mediator of insulin action, compared to normal monkeys. To determine whether the urinary excretion rate of CI was related to insulin resistance, which develops naturally in many obese rhesus monkeys, we examined the relationships between 24-h urinary CI excretion rate and 1) whole body insulin-mediated glucose disposal rates (M) and insulin-mediated changes in 2) the skeletal muscle GS activity ratio (sm delta GSAR), 3) the skeletal muscle glycogen phosphorylase activity ratio, and 4) the adipose tissue GS activity ratio (at delta GSAR) in 27 monkeys ranging from normal (n = 12) to insulin resistant (n = 8) to overtly diabetic (n = 7). The urinary CI excretion rate was significantly correlated with M (r = 0.47; P < 0.02), sm delta GSAR (r = 0.38; P < 0.05), skeletal muscle glycogen phosphorylase activity ratio (r = -0.49; P < 0.01), and at delta GSAR (r = 0.46; P < 0.02). The urinary CI excretion rate was also correlated with glucose tolerance (r = 0.39; P < 0.05). There was a wide range of urinary CI excretion rates (0.42-5.17 mumol/day) in monkeys with normal fasting plasma glucose concentrations. However, of the 7 diabetic monkeys, 6 had a urinary CI excretion rate below 2.0 mumol/day, and in the subgroup of 16 monkeys with a urinary CI excretion rate less than 2.0 mumol/day, the associations of urinary CI with M rate (r = 0.65; P < 0.005), glucose tolerance (r = 0.63; P < 0.01), and sm delta GSAR (r = 0.73; P < 0.001) increased in strength and significance. We propose that the urinary CI excretion rate may be 1) a biochemical indicator of both in vivo and in vitro insulin resistance and 2) a noninvasive diagnostic tool with potential for the identification of those individuals at risk for NIDDM and other related diseases with insulin resistance.     

Region of birth and black diets: the Harlem Household Survey

Human obesity is associated with an increased tumor necrosis factor-alpha (TNF-alpha) mRNA expression in adipose tissue. TNF-alpha decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-alpha may play a role in insulin resistance. In this study, we analyzed plasma levels of TNF-alpha in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. Twenty of the patients had a moderate level of insulin resistance and 20 were severely insulin resistant. The plasma levels of TNF-alpha were higher in patients (4.00+/-1.53 pg/mL in moderately insulin resistant and 4.91+/-1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27+/-0.79 pg/mL, P<0.001). TNF-alpha was significantly related to body mass index, fasting glucose levels, and serum triglyceride levels and inversely related to the high density lipoprotein cholesterol level. The finding of an association between high plasma levels of TNF-alpha and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-alpha may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus.     

Hyperinsulinemia and clustering of cardiovascular risk factors in middle-aged hypertensive Finnish men and women

OBJECTIVE: To examine the relationship between hyperinsulinemia and clusters of cardiovascular risk factors in middle-aged hypertensive patients. DESIGN: A population-based study. SETTING: Pieks?m?ki District Health Center, and the Community health Center of the city of Tampere, in central Finland. SUBJECTS: Hypertensive men and women aged 36, 41, 46, and 51 years (n = 18) in the town of Pieks?m?ki, and a normotensive control population of 177 subjects aged 40 and 45 years in the city of Tampere. MAIN OUTCOME MEASURES: Clusters of obesity (body mass index > 30.0 kg/m2), abdominal adiposity (waist:hip ratio > 1.00 for men and > 0.88 for women), hypertriglyceridemia (> 1.70 mmol/l), a low level of high-density lipoprotein cholesterol (< 1.0 mmol/l in men and < 1.20 mmol/l in women) and abnormal glucose metabolism (impaired glucose tolerance or noninsulin-dependent diabetes as defined by World Health Organization criteria) according to statistical quartiles of the fasting plasma insulin concentration. RESULTS: Among the hypertensives, there was a 2.0- to 3.6-fold higher risk of having a clustering of the insulin-resistance associated cardiovascular risk factors compared with that of the normotensives. Among the hypertensive subjects in the highest quartile of fasting plasma insulin there was a six- to 12-fold increase in risk associated with having two or more insulin resistance-associated cardiovascular risk factors compared with the subjects in the lowest quartile. There was a positive correlation between a high number of ascertained risk factors and high levels of fasting plasma insulin. CONCLUSION: In clinical practice, knowledge of the close relationship between risk-factor cluster status and fasting plasma insulin levels offers a tool to evaluate the occurrence of hyperinsulinemia in middle-aged hypertensive men and women.