Thomas A. Buchanan

A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.

International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy

In the accompanying comment letter (1), Weinert summarizes published data from the Brazilian Gestational Diabetes Study (2) and comments on applying International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel recommendations (3) for the diagnosis of gestational diabetes mellitus (GDM) to that cohort. The Brazilian study provided evidence that adverse perinatal outcomes are associated with levels of maternal glycemia below those diagnostic of GDM by American Diabetes Association or World Health Organization criteria. However, the results were potentially confounded by the treatment of GDM. It did find that women with GDM were at increased risk for some …

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.

COMPLEX DISTRIBUTION, NOT ABSOLUTE AMOUNT OF ADIPONECTIN, CORRELATES WITH THIAZOLIDINEDIONE-MEDIATED IMPROVEMENT IN INSULIN SENSITIVITY

Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates β oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-γ agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in SA (ΔSA) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.

International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy: Response to Weinert

In the accompanying comment letter (1), Weinert summarizes published data from the Brazilian Gestational Diabetes Study (2) and comments on applying International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel recommendations (3) for the diagnosis of gestational diabetes mellitus (GDM) to that cohort. The Brazilian study provided evidence that adverse perinatal outcomes are associated with levels of maternal glycemia below those diagnostic of GDM by American Diabetes Association or World Health Organization criteria. However, the results were potentially confounded by the treatment of GDM. It did find that women with GDM were at increased risk for some …

Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

BACKGROUND Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007). CONCLUSIONS As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

A better index of body adiposity.

Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)–18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual‐energy X‐ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African‐Americans (TARA)” study of African Americans. Correlation between DXA‐derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.

Gestational diabetes mellitus.

BERRY CAMPBELL, M.D. University of South Carolina School of Medicine Division of Maternal Fetal Medicine GESTATIONAL DIABETES: DIAGNOSIS AND MANAGEMENT LEARNING OBJECTIVES: • To identify risk factors for gestational diabetes. • To discuss methods of screening and diagnosis of gestational diabetes. • To discuss the complications of gestational diabetes and pregestational DM. • To discuss the management of diabetes in pregnancy.

Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Placebo-Controlled Trial

Type 2 diabetes mellitus is characterized by two major pathophysiologic defects: insulin resistance and impaired capacity to secrete insulin [1, 2]. A major component of insulin resistance exists in peripheral tissues, where insulins ability to stimulate glucose uptake from the circulation is blunted. During the past three decades, treatment of hyper-glycemia in patients with type 2 diabetes mellitus who do not respond to such behavioral modifications as diet and exercise has focused on improving the relative insulin deficiency through therapy with sulfonylurea drugs to stimulate endogenous insulin secretion or through administration of insulin itself. Two additional drugs have recently become available: metformin, which seems to exert much of its glucose-lowering effect by suppressing hepatic glucose production [3], and acarbose, which changes the pattern of glucose absorption from the gastrointestinal tract [4]. Thus, no pharmacologic intervention for type 2 diabetes mellitus has had a major effect on improving insulin resistance in peripheral tissues. New compounds, the thiazolidinediones, have recently been developed as glucose-lowering agents. Early studies showed that the glucose-lowering effect of thiazolidinediones was evident in animal models of type 2 diabetes mellitus but not those of type 1 diabetes mellitus [5, 6], suggesting that some endogenous insulin secretion is needed for these agents to act. Troglitazone has been shown to decrease levels of not only plasma glucose and glycosylated hemoglobin [7-13] but also insulin and C-peptide. These observations, coupled with direct measures of whole-body insulin sensitivity in a small number of patients with type 2 diabetes mellitus [7], suggest that troglitazone exerts its major glucose-lowering effect by ameliorating insulin resistance. However, it is not clear whether troglitazone exerts its major insulin-sensitizing effect predominantly in the liver or in peripheral tissues. We studied this issue using detailed metabolic measurements in a large group of patients with type 2 diabetes mellitus. Methods This multicenter study was conducted at six sites: University of Chicago, Chicago, Illinois; University of Southern California, Los Angeles, California; University of Rochester, Rochester, New York; University of Pittsburgh, Pittsburgh, Pennsylvania; University of California, San Diego, San Diego, California; and Yale University, New Haven, Connecticut. Sample size was projected on the basis of study design, major end points, and standard power analysis. Each center enrolled patients while adhering to a common protocol with the same inclusion and exclusion criteria. At each center, patients gave written informed consent to participate in the study, which was approved by the respective university human investigation committees. All patients were studied in a 6-month, randomized, placebo-controlled, double-blind protocol. Patients were randomly assigned to treatment according to a blocked randomization code (block size, five) that was generated by a central computer. In each center, study personnel (executors of treatment assignment) and patients were blinded to the treatment code. Patients were consecutively assigned to treatments; equal numbers of troglitazone or matching placebo tablets were dispensed in a double-blind fashion. Patients Patients had to have type 2 diabetes mellitus according to the criteria of the National Diabetes Data Group [14], HbA1c levels above the upper limit of normal, and fasting C-peptide levels of 0.49 nmol/L or greater. Therapy with oral antidiabetic medication was discontinued before randomization. Patients were excluded if they had clinically symptomatic heart disease, had had a vascular occlusive event in the previous 3 months, had had cancer in the past 5 years, had a serum creatinine level greater than 176.8 mol/L, or had serum amino-transferase levels above the upper limit of normal. Study Design After medical screening, a 2-week wash-out period was allowed for discontinuation of therapy with oral antidiabetic medication in patients who were taking such medication. Metabolic studies were done before patients were randomly assigned to one of five treatment groups: 100, 200, 400, or 600 mg of troglitazone daily or placebo. At 6 months, follow-up metabolic studies were repeated 24 hours after patients received the last troglitazone or placebo tablet. At baseline and 6 months, patients were hospitalized and fasted overnight before a meal tolerance test (day 1) and a euglycemic-hyperinsulinemic clamp procedure (day 2) [15]. During the study, patients were prescribed a diet designed to maintain baseline body weight. Dietary assessment at the time of enrollment determined the patients caloric needs [16]. The prescribed diet consisted of 50% carbohydrates, 34% fat (ratio of saturated fat to polyunsaturated fat, 1:4) and 16% protein. Patients were seen at monthly outpatient visits between the baseline and 6-month metabolic studies so that their clinical condition could be monitored. Meal Tolerance Test At approximately 7:00 a.m., patients were placed on bed rest and an intravenous catheter was inserted into an antecubital vein for blood sampling. A small volume of normal saline (0.9%) was infused to maintain patency. At approximately 8:00 a.m., patients ingested a liquid formula meal (Sustacal-HC [Mead Johnson & Co., Evansville, Indiana], which contained 33% of total daily caloric requirements); this was followed 4 hours later by an identical meal. Fasting blood samples were drawn, and additional samples were obtained every hour thereafter for 8 hours. Samples were processed immediately and stored at 80C for measurement of serum levels of glucose, insulin, free fatty acids, and triglycerides and plasma levels of C-peptide. Fasting blood was also drawn for measurement of HbA1c. After completing the test, patients received an evening meal according to their prescribed diet. They then fasted until the end of the euglycemic-hyperinsulinemic clamp procedure the following day. The intravenous line was left in situ for the clamp procedure. Euglycemic-Hyperinsulinemic Clamp Procedure At 6:00 a.m., a 4-hour primed (corrected for ambient fasting plasma glucose level), continuous (2 mg/m2 body surface area per minute) infusion of [6,6- 2H]-glucose (di-deuterated glucose) isotope into the antecubital vein began. During the third hour of infusion, a retrograde cannula was inserted into a contralateral hand vein. The hand was warmed for sampling of arterialized venous blood. A small volume of normal saline (0.9%) was infused through the sampling cannula to maintain patency. Blood samples were drawn at 10-minute intervals during the final 40 minutes of the fourth hour for measurement of plasma glucose and insulin levels and glucose isotope enrichment. After 4 hours of isotope infusion, a two-step priming dose of insulin was administered (480 mU/m2 per minute followed by 240 mU/m2 per minute; each lasted 5 minutes); this was followed by a continuous infusion of insulin (120 mU/m2 per minute) that lasted 300 minutes (total, 5 hours). The plasma glucose level was allowed to decrease to 5.5 mmol/L; exogenous glucose (dextrose, 20 g/100 mL of water enriched to approximately 2.5% with di-deuterated glucose) was then infused to maintain the plasma glucose level, measured every 5 minutes, at 5.5 mmol/L. The basal isotope infusion was stopped when the exogenous glucose infusion began. Patients also received a continuous infusion of potassium (KCl and KPo 4), 0.105 mmol/L per minute, during the insulin infusion to maintain the serum potassium level between 3.5 and 4.5 mmol/L. During the final hour of the clamp procedure, blood samples were drawn every 10 minutes for measurement of plasma insulin levels and steady-state glucose isotope enrichment. For comparison with diabetic patients, eight persons without diabetes (mean age SD, 46 6 years; mean fasting plasma glucose level, 5.3 0.2 mmol/L; mean body mass index, 29 3 kg/m2) were also studied on one occasion under basal and clamped conditions after an identical hyperinsulinemic clamp protocol. Substrate and Hormone Measurements Serum and plasma samples were shipped frozen to Corning Nichols Institute for chemical analysis and to Yale University for measurement of isotope enrichment. Serum total triglyceride levels (Boehringer Mannheim Diagnostics, Indianapolis, Indiana) and plasma free fatty acid levels (NEFA C-test, Wako Chemicals, Richmond, Virginia) were determined enzymatically; interassay coefficients of variation were 2% and 3.6%, and intraassay coefficients of variation were 1.6% and 1%, respectively. Insulin and C-peptide levels were measured by radioimmunoassay (Corning Nichols Institute); the interassay coefficients of variation were 12.3% and 12.0%, and the intraassay coefficients of variation were 7.4% and 6.5%, respectively. Levels of HbA1c were measured by high-performance liquid chromatography using BioRad (Hercules, California) equipment (Corning Nichols Institute), with a normal reference range of 0.045 to 0.059. At each center, plasma glucose levels were measured at the bedside by using a Beckman glucose analyzer (Fullerton, California). Glucose Isotope Data Gas chromatography mass spectrometer analysis of enrichment of di-deuterated glucose in plasma and infusates was done at one center (Yale Stable Isotope Core Facility, New Haven, Connecticut) by using the penta-acetate derivative of glucose [17]. Calculations Basal hepatic glucose production was calculated as follows: Basal hepatic glucose production = (f/sa) x ([enrichmentinf/enrichmentplasma] 1), where f = basal [6,6- 2H] glucose infusion rate (mg/min), sa = body surface area (m2), enrichmentinf = [6,6- 2H] glucose infusate enrichment (%), and enrichmentplasma = steady-state basal plasma [6,6- 2H] glucose enrichment (%). The term enrichment refers to the fraction of isotope of glucose to naturally occurring (native) glucose,

Predicting Future Diabetes in Latino Women With Gestational Diabetes: Utility of Early Postpartum Glucose Tolerance Testing

We tested 32 routine clinical parameters for their ability to discriminate between a high risk and a low risk of non-insulin-dependent diabetes mellitus (NIDDM) within 5–7 years after pregnancies complicated by gestational diabetes mellitus (GDM). Latino women (n = 671) with GDM who did not have diabetes 4–16 weeks after delivery returned for at least one 75-g oral glucose tolerance test (OGTT) within 7.5 years. Multivariate analysis was used to identify parameters ascertained during or immediately after the index pregnancy that were independently associated with the development of diabetes during follow-up. Life table analysis revealed a 47% cumulative incidence rate of NIDDM 5 years after delivery for this cohort of patients who did not have diabetes at the initial postpartum examination. Four variables were identified as independent predictors of NIDDM: the area under the OGTT glucose curve at 4–16 weeks postpartum, the gestational age at the time of diagnosis of GDM, the area under the OGTT glucose curve during pregnancy, and the highest fasting serum glucose concentration during pregnancy. Examination of relative risks (RRs) of NIDDM between the highest and lowest quartiles of the cohort for each variable, adjusted for the other three variables, revealed that the postpartum OGTT provided the best discrimination between high-risk and low-risk individuals (adjusted RR = 11.5 [95% confidence interval 4.5–29.1] compared with adjusted RRs of only 0.5–2.5 for the other three variables). Women who met World Health Organization criteria for impaired glucose tolerance at the early postpartum examination had a 5-year unadjusted 80% risk of diabetes, which was much higher than the risk of NIDDM that has been reported for Latino people with impaired glucose tolerance who were not selected for a history of GDM. Our findings indicate that postpartum glucose tolerance testing is superior to other routine clinical parameters in defining the risk of NIDDM within 5–7 years after pregnancies complicated by GDM. Furthermore, a history of GDM appears to impart a specific risk for NIDDM that cannot be explained by the degree of glucose tolerance observed when patients are not pregnant.