Diabetes Prevention Study Research Articles

Low-dose oral glyburide reduces glucose production rates in patients with impaired fasting glucose

Impaired fasting glucose (IFG) is commonly seen in the US population. Approximately 20% of patients with IFG can progress to develop type 2 diabetes mellitus (DM-2) within 1 year. In the recent diabetes prevention study, lifestyle changes reduced the progression to only 8% per year, and metformin reduced the progression from IFG to DM-2 from 20% to 11% per year. Sulfonylurea therapy in DM-2 increases β-cell function and fails to accelerate the 4% loss in function observed per year. Low-dose sulfonylurea therapy for IFG may be an effective treatment to delay the onset of type 2 diabetes if the treatment does not cause hypoglycemia. A very low dose of glyburide (20 μg/kg body weight) was given orally to 15 nondiabetic volunteers in an attempt to describe its effects on glucose production rates (GPR), blood glucose concentrations, and conterregulatory hormone profile. Six of the volunteers had IFG (mean ± SEM, 115 ± 1.8 mg/dL), and 9 had a normal fasting glucose (NFG) (94 ± 2.3 mg/dL). Fasting blood glucose (FBG) decreased more in IFG after glyburide when compared with the NFG group (29% ± 2.4% v 17% ± 3.5%, P <.05). Patients with IFG had a larger insulin response to glyburide than those with NFG (17.7 ±3 v 10.7 ± 2.9 μU/mL; P <.05). The IFG patients also had a greater decrease in GPR (19% ± 4%) than seen with the normals (12% ± 3%, P <.05). The steeper decrease in GPR may have been due to a greater insulin response to oral glyburide in those with IFG. Low-dose glyburide increases insulin's effect on the liver. Copyright 2003 Elsevier, Inc. All rights reserved.

Signs of beta-cell autoimmunity and HLA-defined diabetes susceptibility in the Finnish population: the sib cohort from the Type 1 Diabetes Prediction and Prevention Study.

To assess the role of HLA-defined genetic diabetes susceptibility in the appearance of signs of beta-cell autoimmunity in a series of children derived from the general population. Tests for five HLA DQB1 alleles and four diabetes-associated autoantibodies were carried out on 1,584 older sibs of infants with an increased HLA-defined genetic risk of Type 1 diabetes. The DQB1 genotypes were classified into those conferring high (* 02/0302), moderate (* 0302/x; where x indicates * 0302 or a non-defined allele), low (* 0301/0302, * 02/0301, * 02/x, * 0302/0602, * 0302/0603; where x indicates * 02 or a non-defined allele) or decreased risk (other genotypes). Both islet cell antibodies (ICA) and GAD65 antibodies (GADA) were more frequent among the sibs with the high-risk genotype than among those with a low or decreased risk. Insulin autoantibodies and IA-2 antibodies (IA-2A) were more prevalent in the high-risk than low-risk sibs. Sibs with moderate-risk genotypes tested positive for ICA, GADA and IA-2A more often than sibs with genotypes conferring decreased risk. Autoantibody titres were also dependent on the genetic risk with high risk sibs having the highest values. Sibs carrying high-risk or moderate-risk genotypes tested positive for multiple antibodies (> or =2) more often than did the sibs with low or decreased genetic risk. The data show that HLA-defined susceptibility to Type 1 diabetes has an effect on both the quality and quantity of humoral beta-cell autoimmunity in unaffected children derived from the general population.

An Integral Role of the Dietitian: Implications of the Diabetes Prevention Program

Obesity and type 2 diabetes have become increasingly prevalent worldwide. Cross-sectional data from the Behavioral Risk Factor Surveillance System indicate that in 2000, over 56% of US adults were overweight, and during the 1990s the proportion of survey participants reporting that they had diabetes rose by 49% (1). Lifestyle changes (increasingly sedentary lifestyle and increasing dietary energy density) have resulted in a dramatic rise in obesity and type 2 diabetes in the developing economies of Latin America as well in the market economies of North America, Europe, and Australia (2). Higher fat diets and increased adiposity have also been linked to a rise in diabetes in Asia, where much of the population develops type 2 diabetes at a lower relative body weight than in Western population groups (2). The worldwide population with diabetes in expected to more than double from an estimated 135 million people in 1995 to 300 million by 2025 (2). Intermediate blood glucose levels between normal and diabetic are associated with insulin resistance and greater risk of macrovascular disease. Impaired glucose tolerance and impaired fasting glucose can be used to classify intermediate glucose values (3). The American Diabetes Association added impaired fasting glucose (defined as a fasting glucose of ≥ 6.1 mmol/L and < 7.0 mmol/L) as a classification in 1997 to more readily identity people with intermediate glucose levels in clinical settings. Studies conducted in Da Qing, China, and in Finland provided early evidence that lifestyle intervention can reduce the risk of developing diabetes in individuals with impaired glucose tolerance. The Da Qing Impaired Glucose Tolerance and Diabetes Study (n = 577) found that diet, exercise, and the combination of diet and exercise appeared to reduce the risk of developing diabetes in people with impaired glucose tolerance (4). The Finish Diabetes Prevention Study (n =523) demonstrated that a lifestyle intervention could reduce the risk of developing diabetes by 58% in individuals with impaired glucose tolerance over a 3.2-year follow-up (5). The Diabetes Prevention Program (DPP) was a large (n = 3, 234), 27-center rendomized clinical trial to evaluate the safety and efficacy of interventions in delaying or preventing diabetes in diverse populations of high-risk individuals in the United States (6).

Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.

Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.

Relative and absolute HLA-DQA1-DQB1 linked risk for developing type I diabetes before 40 years of age in the Belgian population: implications for future prevention studies

HLA-DQ genotyping remains the cornerstone of genetic risk stratification in type I diabetes prediction and prevention studies. We developed a genetic screening strategy for predisposition to type I diabetes in the Belgian population based upon HLA-DQA1-DQB1 typing and taking into account the age at clinical onset. A group of 1866 autoantibody-positive type I patients below age 40 years recruited by the Belgian Diabetes Registry and a group of 750 control subjects were DQA1-DQB1 genotyped. In the total study population 16 different DQA1-DQB1 haplotypes were revealed, allowing the stratification of 81 genotypes in ten different genotype groups. Apart from the highest risk DQA1∗-DQB1∗ genotype 0301-0302/0501-0201 (odds ratio 21; absolute risk 6%), three other genotype groups conferred a highly significant disease risk (p < 10−6). Altogether, these susceptibility genotypes were carried by 9% of the control subjects versus 60% of the patients diagnosed before age 40 years and up to 70% of those under age 5 years. All other genotypes were protective, neutral, infrequent or associated with a moderate protection or susceptibility. A strong, although not absolute protection was conferred by DQB1∗0602-positive haplotypes (odds ratio = 0.03). This study in a large cohort of autoantibody-positive patients shows that a DQA1-DQB1-based genotyping strategy allows the identification of a subgroup representing less than 10% of the Belgian population but harbouring the majority of future type I patients arising in childhood or early adulthood. Future prediction and prevention studies should take into account the age dependency of this HLA-DQ associated risk.

Changes in diet and physical activity prevented type 2 diabetes mellitus in people with impaired glucose tolerance

(2001) N Engl J Med 344, 1343. Tuomilehto J, Lindström J, Eriksson JG, et al, . for the Finnish Diabetes Prevention Study Group. . Prevention of type 2 diabetes mellitus...

The First Signs of -Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study

The First Signs of -Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study

The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study.

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

Evaluation of the insulin resistance syndrome in 5- to 10-year-old overweight/obese African-American children.

To characterize the insulin sensitivity of overweight and obese 5- to 10-year-old (Tanner stage 1-3) African-American children screened for participation in a diabetes prevention study and to identify the association of insulin sensitivity with obesity, hyperlipidemia, and hypertension. Measures of insulin resistance (homeostasis model assessment) and insulin sensitivity (Matsuda and DeFronzo's whole-body insulin sensitivity) were calculated from a 2-h oral glucose tolerance test in 137 African-American children recruited into a diabetes prevention study. Measures of lipids (LDL, HDL, total cholesterol, and triglycerides), blood pressure, and body composition were obtained for a subset of the children. In response to a glucose challenge, girls and older and heavier children produced significantly more insulin. As BMI increased, there was a statistically significant decrease in insulin sensitivity, particularly in girls. Insulin sensitivity was inversely correlated with increases in blood pressure, triglycerides, subcutaneous fat, the percentage of total body fat, and Tanner stage, but it was not correlated with LDL and HDL. Reduced insulin sensitivity and the cluster of risk factors known as the insulin resistance syndrome (IRS) are already apparent in these overweight African-American children. Young African-American girls, in particular, already show evidence of hyperinsulinemia in response to a glucose load, suggesting that the early stages of metabolic decompensation that lead to type 2 diabetes are already occurring. Monitoring of those risk factors known to be part of IRS should become part of routine medical care for overweight or obese African-American children.

Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.

Previous studies suggest that enterovirus infections may initiate and accelerate beta-cell damage years before the clinical manifestation of type 1 diabetes. We have now analyzed the role of enterovirus infections in the initiation of autoimmunity in children who have tested positive for diabetes-associated autoantibodies in a prospective study starting at birth (the Finnish Diabetes Prediction and Prevention Study). The frequency of enterovirus infections was studied using both serology and testing for the presence of enterovirus RNA in the sera of 21 children who developed and retained autoantibodies and in 104 control subjects chosen from the same study cohort and matched for the time of birth, sex, and HLA alleles determining genetic diabetes susceptibility. Sample intervals were taken as basic units of follow-up, to which the observed number of infections was adjusted. Enterovirus infections were detected in 26% of sample intervals in the case subjects and in 18% of the sample intervals in the control children (P = 0.03). A temporal relationship between enterovirus infections and the induction of autoimmunity was found; enterovirus infections were detected in 57% of the case subjects during a 6-month follow-up period preceding the first appearance of autoantibodies compared with 31% of the matched control children in the same age-group (odds ratio 3.7, 95% CI 1.2-11.4). The frequency of adenovirus infections did not differ between the patient and control groups. Our data imply that enterovirus infections are associated with the development of beta-cell autoimmunity and provide evidence for the role of enteroviruses in the initiation of beta-cell destruction.

Geographical differences within Finland in the frequency of HLA‐DQ genotypes associated with Type 1 diabetes susceptibility

Geographical variations in the HLA-DQ genotypes associated with risk for type 1 diabetes were evaluated in Finland. Samples of 280 diabetic children diagnosed in Turku (south-west of the country) and 405 in Oulu (north of the country) were studied as well as a series of 14 096 and 10 016 newborns collected from the same hospitals. There were no major differences in the risk or protection conferred by various HLA-DQB1 genotypes between south-western and northern parts of the country when genotypes of children with type 1 diabetes from these two centres were compared with those of newborns, representing the background populations. However, the distribution of various genotypes was different, both in diabetic children and in newborns, when compared between the two regions (P < 0.0001, chi2 test). These differences reflected the allele frequencies in newborn cohorts in which HLA-DQB1*02 and DQB1*0301 were found more often in Turku and DQB1*0302 more often in Oulu (P < 0.0001 for all differences). Similar types of differences were detected when children who were diagnosed as having diabetes during the national 'Childhood Diabetes in Finland' (DiMe) study between the years 1986-1989 were compared according to their residence. The observed differences in genotype and allele frequencies demonstrate the heterogeneity for HLA alleles even in a population that is generally regarded as highly homogeneous. These differences also affect the sensitivity and efficiency of the screening programme used for identifying infants with genetic susceptibility to IDDM in the ongoing Finnish Diabetes Prediction and Prevention Study.

Care giver perception of children's obesity-related health risk: a study of African American families.

To examine care giver perception of children's weight-related health risk in African American families. One-hundred and eleven families (representing 48 boys and 63 girls) screened for participation in a diabetes prevention study participated. Care givers completed a health awareness questionnaire that assessed their perception of the child's weight, eating habits, appearance, exercise habits, and health risk. The care givers also reported each subject's family history of obesity, diabetes, and other chronic diseases. After a physical examination, height and weight were used to compute an age- and sex-adjusted body mass index for each child. Despite the fact that a substantial number of children were obese (57%) and super-obese (12%), only 44% of the care givers perceived the child's weight to be a potential health problem. Regression analysis showed that 21% of the variance in parental perception of obesity-related health risk could be predicted by child age, body mass index, perception of frame size, and perception of exercise habits. A number of reasons for the apparent minimization of child health risk are discussed, including cultural differences in the acceptance of a large body habitus, lack of knowledge about the connection between childhood obesity and future health risk, and an optimistic bias in the perception of personal health risk.

The effect of aldose reductase inhibitor Statil (ICI 128436) on the glucose over-utilization in kidney of diabetic rats

The present study examined the effect of the aldose reduetase inhibitor Statil (ICI 128436, ICI, Cheshire, U.K.) on the levels of metabolites and activities of enzymes involved in the glycolysis, polyol pathway and pentose phosphate pathway and on the flux of radioactive glucose through these pathways in kidney of streptozotocin diabetic rats. In kidneys of diabetic rats of 30 days duration the level of sorbitol was increased by + 82% and fructose concentration was raised by + 42%. After treatment with Statil for 9 days (reversal study) a significant fall in kidney sorbitol concentration and kidney fructose concentration was found. Lactate and UDP-glucose concentrations which were both significantly raised in diabetes by +80% and +23% respectively decreased by 20% after Statil treatment, together with a decline in UDP-glucose dehydrogenase activity. Aldose reductase and sorbitol dehydrogenase activities were also significantly lowered by Statil. In the reversal study there was no significant effect of Statil on the flux of glucose via alternative routes in the kidney cortex. In kidneys of diabetic rats of 9 days duration, the level of sorbitol increased by +61% and the concentration of fructose was raised by + 30%. The treatment with Statil (25 mg/kg) from the day of induction of diabetes (prevention study) prevented the accumulation of sorbitol, fructose and UDP-glucose. The increase in the incorporation of radioactive glucose through the pentose phosphate pathway seen in diabetes was less marked in the renal cortex of diabetic rats treated with Statil ab initio.