Using faecal elastase-1 to screen for chronic pancreatitis in patients admitted with acute pancreatitis.

BACKGROUND: Patients presenting with acute pancreatitis may have co-existing chronic pancreatitis, the accurate diagnosis of which would potentially guide appropriate management. Gold standard tests are often invasive, costly or time-consuming, but the faecal elastase-1 assay has been shown to be comparatively accurate for moderate and severe exocrine deficiency. This study aimed to evaluate fecal elastase-1 concentration [FE-1] against clinical criteria for chronicity in an acute setting. PATIENTS AND METHODS: [FE-1] was performed on patients admitted with acute onset of epigastric pain and a serum lipase at least three times the upper limit of normal. Clinical diagnosis of chronic pancreatitis was defined by the presence of specific clinical, pathological or radiological criteria. A [FE-1] value of <200 microg/g was similarly considered indicative of chronic exocrine insufficiency. Thus a 2 x 2 table comparing [FE-1] and clinical diagnosis was constructed. RESULTS: After exclusion of liquid stool specimens, 105 stool specimens from 87 patients were suitable for [FE-1] determination. [FE-1] was evaluated against the clinical diagnosis of chronic pancreatitis, initially for the whole sample, and then after exclusion of cases of moderate and severe acute pancreatitis (Ranson score >2). The latter analysis, based on an exocrine insufficiency threshold of 200 microg/g, yielded a sensitivity of 79.5%, specificity of 98.0%, positive predictive value of 96.9% and negative predictive value of 86.0%. CONCLUSION: [FE-1] is an accurate screening tool for underlying chronic exocrine insufficiency when taken in the course of a hospital admission for mild acute pancreatitis.

Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53).

AIMS: The beta-cell ATP-sensitive potassium channel consists of two subunits, SUR1 and Kir6.2. Population association studies have shown that three variants in SUR1 and one in Kir6.2 are associated with Type 2 diabetes. These polymorphisms do not result in a functional change or affect splicing, suggesting that they could be in linkage disequilibrium with a pathogenic mutation. The present study aimed firstly to screen the promoter regions of SUR1 and Kir6.2 to determine whether mutations in linkage disequilibrium with the silent variants lie in regulatory regions, which might lead to changes in gene expression. Secondly, novel and previously described variants associated with Type 2 diabetes (SUR1 exon 16-3t, exon 18 T, and Kir6.2 E23K) were investigated in the UKPDS cohort. METHODS: The promoter sequences of both genes were screened by single-stranded conformational polymorphism analysis for variants associated with Type 2 diabetes. The previously reported variants were evaluated in 364 Type 2 diabetic and 328 normoglycaemic control subjects. RESULTS: Two variants were detected in the SUR1 promoter, a three base insertion (caa) at -522 bp and a single base substitution at - 679 bp (c-->g). Neither of the variants were associated with diabetes, nor were they in a sequence consensus region for transcription factors. No association with diabetes was observed for either SUR1 variant. However, in contrast, analysis of the Kir6.2 E23K variant showed that the KK homozygosity was more frequent in Type 2 diabetic than control subjects. Variants were not associated with clinical characteristics nor did they affect response to sulphonylurea therapy CONCLUSION: There is no support at present for mutations in either Kir6.2 or SUR1 promoter sequences contributing to Type 2 diabetes. However, the minimal promoter region of SUR1 has yet to be investigated. The E23K variant of Kir6.2 is associated with Type 2 diabetes mellitus in the UKPDS cohort.

UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis.

AIMS/HYPOTHESIS: To determine risk factors related to the incidence and progression of diabetic retinopathy over 6 years from diagnosis of Type II (non-insulin-dependent) diabetes mellitus. METHODS: This report describes 1919 patients from within the United Kingdom Prospective Diabetes Study (UKPDS), with retinal photographs taken at diagnosis and 6 years later and with complete data available. Photographs were centrally graded for lesions of diabetic retinopathy using the modified Early Treatment of Diabetic Retinopathy Study Final scale. Risk factors were assessed after 3 months diet from the time of diagnosis of diabetes. Patients were seen every 3 months in a hospital setting. Biochemical measurements were done by a central laboratory. End points of vitreous haemorrhage and photocagulation were confirmed by independent adjudication of systematically collected clinical data. The main outcome measures were incidence and progression of retinopathy defined as a two-step Early Treatment of Diabetic Retinopathy Study (ETDRS) final scale change. RESULTS: Of the 1919 patients, 1216 (63 %) had no retinopathy at diagnosis. By 6 years, 22 % of these had developed retinopathy, that is microaneurysms in both eyes or worse. In the 703 (37 %) patients with retinopathy at diagnosis, 29 % progressed by two scale steps or more. Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over 6 years, higher blood pressure and with not smoking. In those who already had retinopathy, progression was associated with older age, male sex, hyperglycaemia (as evidenced by a higher HbA1c) and with not smoking. CONCLUSION/INTERPRETATION: The findings re-emphasise the need for good glycaemic control and assiduous treatment of hypertension if diabetic retinopathy is to be minimised.

Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45). UK Prospective Diabetes Study Group.

AIMS: To assess the effect of diet on fasting plasma lipids and lipoproteins in patients with newly diagnosed Type 2 diabetes. METHODS: A total of 2,906 patients each underwent 3 months' diet therapy before allocation to therapy in a randomized controlled clinical trial. Lipids and lipoproteins were measured at diagnosis and after 3 months' diet. RESULTS: The mean body weight at diagnosis was 83 kg. Weight decreased after diet by a mean of 4.5 kg; body mass index (BMI) decreased by 1.51 kg/m2; plasma glucose fell by 3 mmol/l from 11 mmol/l; and HbA1c by 2% from 9%. Triglyceride concentrations were reduced in men by -0.41 (95% confidence interval (CI) -0.47 to - 0.35) mmol/l from a geometric mean 1.8 (1 SD interval 1.0-3.0) mmol/l, and in women by -0.23 (-0.28 to -0.18) mmol/l from a similar level. Cholesterol decreased in men by -0.28 (-0.33 to -0.24) mmol/l from 5.5 (1.1) mmol/l, and in women by -0.09 (-0.14 to -0.04) mmol/l from 5.8 (1.2) mmol/l with corresponding changes in LDL cholesterol. HDL cholesterol increased in men by 0.02 (0.01 to 0.04) mmol/l and in women by 0.01 (0 to 0.02) mmol/l. Triglyceride concentration in the top tertile was reduced by 37% in men (> 2.1 mmol/l) and by 23% in women (> 2.2 mmol/l) with regression to mean accounting for 13% and 6%, respectively. Similarly cholesterol in the top tertile was reduced by 12% in men (> 5.8 mmol/l) and 7% in women (> 6.2 mmol/l) with 6% of the decrease in both men and women accounted for by regression to the mean. CONCLUSIONS: Initial dietary therapy in patients with newly diagnosed Type 2 diabetes substantially reduced plasma triglyceride, marginally improved total cholesterol and subfractions, and resulted in a potentially less atherogenic profile, although this did not eliminate the excess cardiovascular risk in patients with Type 2 diabetes.

Parallel changes of proinsulin and islet amyloid polypeptide in glucose intolerance.

Elevated proinsulin secretion and islet amyloid deposition are both features of Type 2 diabetes but their relationship to beta-cell dysfunction is unknown. To determine if islet amyloid polypeptide (IAPP) secretion is disproportionate with other beta-cell products at any stage of glucose intolerance, 116 subjects were studied. Non-diabetic subjects with equivalent body mass index (BMI) were assigned to three groups, (i) normal fasting glucose, fpg<5.5 mmol l(-1); (ii) intermediate fasting glucose, fpg> or =5.5<6.15 mmol l(-1); (iii) impaired fasting glucose (IFG), fpg> or =6.1<7.0 mmol l(-1). Diabetic subjects were divided according to therapy (9 diet, 19 tablet, and 11 insulin). IAPP, C-peptide and proinsulin were measured fasting and at the end of a 1-h glucose infusion. Fasting C-peptide, IAPP and proinsulin were significantly elevated in the IFG group compared with the other non-diabetic groups (P<0.02); fasting IAPP/C-peptide and proinsulin/C-peptide were 1-2% in all non-diabetic groups. Fasting and 1-h proinsulin and proinsulin/C-peptide were higher in diabetic compared with non-diabetic subjects (P<0.01). IAPP and IAPP/C-peptide in diabetic groups were similar to that in non-diabetic subjects but reduced in the insulin-treated group (P<0.01). Proinsulin was disproportionately increased compared with C-peptide and IAPP in Type 2 diabetes particularly in severe beta-cell failure implying more than one concurrent beta-cell pathology.

Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects.

The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxybutyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period. The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p= 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p=0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p=0.0017) and insulin measured on the same day (p=0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however.

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

OBJECTIVE: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes. RESULTS: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%).

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.

OBJECTIVE: To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. RESULTS: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.

The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.

Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes.

Adequate comparisons of the relative performance of different tests of beta-cell function are not available. We compared discrimination of commonly used in vivo tests of beta-cell function across a range of glucose tolerance in seven subjects with normal glucose tolerance (NGT), eight subjects with impaired glucose tolerance (IGT), and nine subjects with type 2 diabetes. In random order, each subject underwent two of each of the following tests: 1) frequently sampled 0.3-g/kg intravenous glucose tolerance test (FSIVGTT) with MinMod analysis; 2) homeostasis model assessment (HOMA) from three samples at 5-min intervals with a model incorporating immunoreactive or specific insulin measurements; and 3) continuous infusion of 180 mg x min(-1) x m(-2) glucose with model assessment (CIGMA) of three samples at 50, 55, and 60 min (1-h CIGMA) and at 110, 115, and 120 min (2-h CIGMA). The discrimination of each test was assessed by the ratio of the within-subject SD to the underlying between-subject SD, the discriminant ratio (DR). The degree to which tests measured the same physiological variable was assessed using Pearson's correlation coefficient adjusted for attenuation due to test imprecision. An unbiased line of equivalence, taking into account the imprecision of both tests, was used to compare results. Beta-cell function assessed from HOMA and beta-cell function assessed from CIGMA (CIGMA%beta) (using immunoreactive insulin) had higher DRs than first-phase intravenous glucose tolerance test-derived incremental insulin peak, area, insulin-to-glucose index, and acute insulin response to glucose from FSIVGTT-MinMod. CIGMA%beta (immunoreactive insulin) had the highest DR. FSIVGTT-derived first-phase insulin response tests correlated only moderately with HOMA and CIGMA. Using specific rather than immunoreactive insulin for HOMA and CIGMA did not improve discriminatory power. Simple tests such as HOMA and CIGMA, using immunoreactive insulin, offer better beta-cell function discrimination across subjects with NGT, IGT, and type 2 diabetes than measurements derived from FSIVGTT first-phase insulin response.

Microaneurysms in the development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study Group.

AIMS/HYPOTHESIS: To determine whether microaneurysms, in the absence of other lesions, have a predictive role in the progression of diabetic retinopathy in Type II (non-insulin-dependent) diabetes mellitus. METHODS: Retinal photographs taken at diagnosis in patients participating in the United Kingdom Prospective Diabetes Study, and thereafter at 3 yearly intervals, were assessed using a modified Early Treatment of Diabetic Retinopathy grading system for lesions of diabetic retinopathy and end points of vitreous haemorrhage and photocoagulation. The number of microaneurysms in each eye was recorded. RESULTS: The changes between diagnosis and later photographs were analysed in 2424 patients at 6 years, 1236 at 9 years and 414 at 12 years. Of the 2424 patients studied in the 6 year cohort 1809 had either no retinopathy or microaneurysms only at entry. In these patients the presence of microaneurysms alone and also the number of microaneurysms had a high predictive value for worsening retinopathy at 3, 6, 9, and 12 years after entry into the study (e. g. at 6 years chi(2) for trend = 75 on 1 df, p < 0.001). The predictive value of the presence or absence of microaneurysms and their number at 3 years from diagnosis and subsequent worsening retinopathy was similar to that at entry. CONCLUSION/INTERPRETATION: Microaneurysms are important lesions of diabetic retinopathy and even one or two microaneurysms in an eye should not be regarded as unimportant.

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.

CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes.

AIMS/HYPOTHESIS: Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. METHODS: Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio - DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. RESULTS: Reciprocal fasting plasma insulin (FPI(-1)), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI(-1), HOMA %S, 2-h CIGMA %S and S(I) FSIVGTT intercorrelated more than 90% of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. CONCLUSION/INTERPRETATION: The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative.

A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44)

OBJECTIVE: To determine the degree to which alpha-glucosidase inhibitors, with their unique mode of action primarily reducing postprandial hyperglycemia, offer an additional therapeutic approach in the long-term treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 1,946 patients (63% men) who were previously enrolled in the U.K. Prospective Diabetes Study (UKPDS). The patients were randomized to acarbose (n = 973), titrating to a maximum dose of 100 mg three times per day, or to matching placebo (n = 973). Mean +/- SD age was 59 +/- 9 years, body weight 84 +/- 17 kg, diabetes duration 7.6 +/- 2.9 years, median (interquartile range) HbA1c 7.9% (6.7-9.5), and fasting plasma glucose (FPG) 8.7 mmol/l (6.8-11.1). Fourteen percent of patients were treated with diet alone, 52% with monotherapy, and 34% with combined therapy. Patients were monitored in UKPDS clinics every 4 months for 3 years. The main outcome measures were HbA1c, FPG, body weight, compliance with study medication, incidence of side effects, and frequency of major clinical events. RESULTS: At 3 years, a lower proportion of patients were taking acarbose compared with placebo (39 vs. 58%, P < 0.0001), the main reasons for noncompliance being flatulence (30 vs. 12%, P < 0.0001) and diarrhea (16 vs. 8%, P < 0.05). Analysis by intention to treat showed that patients allocated to acarbose, compared with placebo, had 0.2% significantly lower median HbA1c at 3 years (P < 0.001). In patients remaining on their allocated therapy, the HbA1c difference at 3 years (309 acarbose, 470 placebo) was 0.5% lower median HbA1c (8.1 vs. 8.6%, P < 0.0001). Acarbose appeared to be equally efficacious when given in addition to diet alone; in addition to monotherapy with a sulfonylurea, metformin, or insulin; or in combination with more complex treatment regimens. No significant differences were seen in FPG, body weight, incidence of hypoglycemia, or frequency of major clinical events. CONCLUSIONS: Acarbose significantly improved glycemic control over 3 years in patients with established type 2 diabetes, irrespective of concomitant therapy for diabetes. Careful titration of acarbose is needed in view of the increased noncompliance rate seen secondary to the known side effects.

Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29.

OBJECTIVE: To investigate modifiable and nonmodifiable risk factors for stroke in type 2 diabetes mellitus. PATIENTS AND METHODS: A total of 3776 patients aged 25 to 65 years newly diagnosed as having type 2 diabetes mellitus without known cardiovascular or other serious disease were studied for a median of 7.9 years. An initial stepwise evaluation of risk factors was done in 2704 patients with all risk factors measured, with the final Cox model analysis being of 3776 patients who had complete data on the selected variables. RESULTS: Of 3776 patients, 99 (2.6%) had a stroke. Significant risk factors for stroke in a multivariate model were age (estimated hazard ratio [95% confidence interval], 4.78 [2.56-8.92] for > or =60 vs <50 years), male sex (1.63 [1.08-2.47)] vs female), hypertension (2.47 [1.64-3.74)] vs normotension), and in 3728 patients who had electrocardiography at study entry, atrial fibrillation (8.05 [3.52-18.44] vs sinus rhythm). Obesity, lack of exercise, smoking, poor glycemic control, hyperinsulinemia, dyslipidemia, and microalbuminuria were not significantly associated with stroke in the model. CONCLUSION: In patients with type 2 diabetes, aggressive antihypertensive therapy and routine anticoagulation therapy for atrial fibrillation may reduce the risk of stroke.

Knowledge of risk of developing diabetes mellitus among siblings of Type 2 diabetic patients.

AIMS: We set out to investigate the extent to which siblings of diabetic subjects perceived themselves likely to develop Type 2 diabetes mellitus (DM) when offered screening tests. METHODS: Nondiabetic siblings, aged 35-74 years, of Type 2 diabetic patients who were more than 35 years old at diagnosis had fasting plasma glucose measured in a study to determine heritability of diabetes. Questionnaires assessing perceived likelihood of developing, seriousness and knowledge about diabetes were completed. Logistic regression assessed factors predicting perceptions of diabetes risk. RESULTS: Factors predicting diabetes on screening were male sex, increasing age and body mass index (BMI) > or = 30. Eighty-nine per cent of 540 eligible siblings completed questionnaires. Thirty-eight per cent saw themselves at increased risk of diabetes and 34% thought diabetes a serious problem. Predictors of perceiving an increased likelihood of developing diabetes were female sex, age 35-54 years vs. 55-74 years and having a parent with diabetes. BMI did not affect perceptions of likelihood. CONCLUSION: A perception of reduced vulnerability to diabetes may occur due to unawareness of risk or minimization of risk. Feelings of invulnerability may affect emotional response to a subsequent result. It is not known whether providing more information about the risk of developing diabetes prior to screening would affect outcomes

Within- and between-subject variation in commonly measured anthropometric and biochemical variables.

BACKGROUND: The biological variation of some commonly assessed metabolic variables in healthy subjects has not been studied extensively. The aim of the study was to assess, in 12 healthy subjects (6 male and 6 female; mean (SD) age; 22.7 (1.5) years) following an overnight fast, the day-to-day variation of body fat (impedance method), triglycerides, nonesterified fatty acid (NEFAs), glycerol, 3-hydroxybutyrate (3-OHB), lactate, glucose, insulin (RIA), C-peptide, and glucagon on 12 consecutive days. METHODS: Between- and within-subject coefficients of variation (CVG and CVW) were estimated using a random effects analysis of variance, and assay variation was subtracted to give the coefficient of within-subject biological variation (CVI). Individuality indices were calculated as CVW/CVG. RESULTS: The overall means, CVI, and individuality indices were as follows: for body fat, 24.2%, 10%, and 0.3; for triglycerides, 0.61 mmol/L, 21%, and 1.1; for NEFAs, 376 micromol/L, 45%, and 1.4; for glycerol, 48 micromol/L, 36%, and 0.8; for 3-OHB, 43 micromol/L, 61%, and 1.5; for lactate, 0.88 mmol/L, 31%, and 1.1; for glucose, 4.9 mmol/L, 4.8%, and 0.7; for insulin, 52 pmol/L, 26%, and 1.0; for C-peptide, 0.39 nmol/L, 24%, and 0.9; and for glucagon, 53 ng/L, 19%, and 0.8. CONCLUSIONS: The data presented here are necessary for the evaluation of several important metabolic variables in individual and group studies. The biological variation of some metabolites makes it difficult to characterize the status of healthy subjects with a single measurement.