Erectile dysfunction is a strong predictor of poor quality of life in men with Type 2 diabetes mellitus.

AIMS: To identify predictors of poor quality of life among men with diabetes from a comprehensive set of sexual, clinical, socio-economic and lifestyle variables. METHODS: This was a cross-sectional observational-study of 253 men with Type 2 diabetes, randomly selected from a clinic in Colombo, Sri Lanka. Erectile dysfunction was assessed using the five-item International Index of Erectile Function and quality of life was assessed using the Sri Lankan version of the 36-item short form health survey questionnaire and the disease-specific Psychological Impact of Erectile Dysfunction scale. The presence of premature ejaculation, reduced libido, socio-demographic and lifestyle data was obtained using an interviewer-administered questionnaire. Significant predictors of quality of life were identified by stepwise multivariate linear regression models for short form-36 subscales, summary scales and two scales of Psychological Impact of Erectile Dysfunction. RESULTS: Significant predictors on the physical summary scale of the 36-item short form were erectile dysfunction (ß = 7.93, 95% CI 3.70-12.17, P < 0.001) and reduced libido (ß = 5.20, 95% CI 0.82-9.59, P < 0.05). Predictors on the mental health summary scale of the 36-item short form were erectile dysfunction (ß = 5.82, 95% CI 2.26-9.37, P < 0.01), BMI > 27.5 kg/m(2) (ß = 9.12, 95% CI 1.38-17.44, P < 0.05), ischaemic heart disease (ß = 6.39, 95% CI 0.74-12.04, P < 0.05) and insulin therapy (ß = 5.28, 95% CI 0.34-10.22, P < 0.05). Significant predictors in the sexual experience scale of the Psychological Impact of Erectile Dysfunction were erectile dysfunction (ß = 6.57, 95% CI 4.63-8.51, P < 0.001), reduced libido (ß =4.33, 95% CI 2.34-6.32, P < 0.001) and postural hypotension (ß = 3.99, 95% CI 0.13-7.85, P < 0.05). Predictors on the emotional life scale of the Psychological Impact of Erectile Dysfunction were erectile dysfunction (ß = 2.96, 95% CI 1.37-4.58, P < 0.001), reduced libido 2.75 (ß = 2.75, 95% CI 1.12-4.40, P < 0.01), younger age (ß = 1.05, 95% CI 0.35-1.75, P < 0.01) and postural hypotension (ß = 3.39, 95% CI 0.35-6.45, P < 0.05). CONCLUSION: Erectile dysfunction was a strong predictor of poor generic and disease-specific quality of life among other sexual and clinical variables in men with diabetes.

Validity of simplified protocols to estimate glomerular filtration rate using iohexol clearance.

BACKGROUND: Iohexol clearance is an accurate and precise exogenous marker of glomerular filtration rate (GFR), but protocols are generally lengthy or require multiple sampling. Shorter or simpler protocols would be more practicable. METHODS: Two clearance estimates, two weeks apart, were undertaken in 11 healthy individuals and 26 diabetic patients with minimal to moderate renal impairment (chronic kidney disease stages 1-3). Blood specimens withdrawn at 60, 90, 120, 150, 180 and 240 min post-iohexol were analysed for iohexol. RESULTS: Visit 1 demonstrated excellent correlation with visit 2 (slope 1.00, confidence interval [CI] 0.88 to 1.13, intercept 0.94 mL/min/1.73 m(2), CI -9.9 to 11.8, P=0.43). The within-individual coefficient of variation (CV) of the 240 min reference method was 5.4% at a mean GFR of 84.1 mL/min/1.73 m(2). Single point estimates between 120 and 240 min had CVs of 4.5-7.0%, and did not differ from the reference method CV by more than 2.0 mL/min/1.73 m(2). Two and three point estimates in the interval 60-120 min post iohexol injection offered no advantages over these single-point estimates and overestimated at lower GFRs. CONCLUSIONS: An iohexol clearance estimate of GFR derived from a single sample taken between 2 to 4 h after infusion may provide a suitable tool for routine clinical use.

Use of the reverse shoulder prosthesis for the treatment of failed hemiarthroplasty in patients with glenohumeral arthritis and rotator cuff deficiency.

We report the use of the reverse shoulder prosthesis in the revision of a failed shoulder hemiarthroplasty in 19 shoulders in 18 patients (7 men, 11 women) with severe pain and loss of function. The primary procedure had been undertaken for glenohumeral arthritis associated with severe rotator cuff deficiency. Statistically significant improvements were seen in pain and functional outcome. After a mean follow-up of 44 months (24 to 89), mean forward flexion improved by 26.4 degrees and mean abduction improved by 35 degrees . There were six prosthesis-related complications in six shoulders (32%), five of which had severe bone loss of the glenoid, proximal humerus or both. Three shoulders (16%) had non-prosthesis related complications. The use of the reverse shoulder prosthesis provides improvement in pain and function for patients with failure of a hemiarthroplasty for glenohumeral arthritis and rotator cuff deficiency. However, high rates of complications were associated with glenoid and proximal humeral bone loss.

Continuous glucose monitoring detected hypoglycaemia in the Treating to Target in Type 2 Diabetes Trial (4-T).

AIMS: Hypoglycaemia is a significant risk in insulin treated type 2 diabetes and has been associated with future risk of cardiovascular events. We compared the frequency of low-glucose events using continuous glucose monitoring (CGM) with that of self-reported hypoglycemic events at the end of the first and third years of the Treating to Target in Type 2 Diabetes Trial (4-T), which compared biphasic, prandial and basal insulin regimens added to sulfonylurea and metformin. METHODS: CGM using a Medtronic Gold system was performed in a subgroup of 4-T participants. CGM detected low-glucose events were defined at thresholds of ≤3.0 (CGM3.0) and ≤2.2 (CGM2.2) mmol/l. RESULTS: Of the 110 participants, 106 and 70 had CGM analysable data at the end of years 1 and 3 respectively. In both years, the frequency of CGM detected low glucose events was several fold higher than that of self-reported hypoglycaemia (symptoms with blood glucose less than 3.1mmol/l [<56mg/dl]). At the end of the first year, CGM3.0 and CGM2.2 mean (95%CI) event frequencies, expressed at events per participant per year, were 120 (85, 155) and 41 (21, 61) compared with 17 (8, 29) self-reported events during CGM, each p=0.001. The disparity at the end of the third year was similar. CONCLUSIONS: These data demonstrate the likely under-reporting of hypoglycaemia and of potential hypoglycaemia unawareness in clinical trials. The clinical implications of these findings need to be explored further (ISRCTN No ISRCTN51125379).

Normal proinsulin responses to glucose in mild type II subjects with subnormal insulin response.

IPI, 32-33 SPI, and insulin were measured by specific assays and related to plasma glucose and BMI in diet-treated type II diabetic subjects (FPG 7.3 +/- 1.8 mM) and nondiabetic control subjects, both fasting and during a 12-mM hyperglycemic clamp. In both groups, BMI correlated with fasting plasma insulin (rs = 0.76, P < 0.001 and 0.50, P < 0.01, respectively) and IPI (rs = 0.49, P = 0.03 and rs = 0.69, P < 0.001, respectively). Accounting for obesity, fasting plasma insulin was subnormal in diabetic subjects (58% of control group, 1 SD range, 49-68%), but did not correlate with FPG. In contrast, fasting plasma IPI correlated with FPG in the diabetic patients (rs = 0.47, P < 0.05). In all subjects, 64% of the variance in plasma IPI was explained by BMI and FPG. Fasting 32-33 SPI was similar in the two groups. In response to a hyperglycemic clamp, the diabetic subjects had subnormal insulin concentrations (geometric means 71 and 214 pM, P < 0.001), but normal IPI concentrations (11.6 and 14.2 pM, respectively). Reduction of 32-33 SPI concentrations in diabetic subjects was intermediate (7.3 and 13.2 pM, P < 0.05). In diabetic subjects both fasting and clamp responses were subnormal for insulin but apparently normal for IPI. The major defect in pancreatic function is an impaired insulin response to glucose, and this, rather than an increase in proinsulin secretion, gives rise to the relative increase in proinsulin.

Type II diabetes: clinical aspects of molecular biological studies.

Type II diabetes remains a genetic nightmare. The major problem is identifying suitable pedigrees, sib-pairs, and populations for study. Segregation analysis data suggest that type II diabetes is likely to be polygenic, although one or more major genes could also be involved. This and the high prevalence of diabetes affect the strategies for searching for genetic mutations. Linkage analysis in classical type II diabetes pedigrees is unlikely to be successful. In addition, affected sib-pair analysis is limited because both parents are often affected, leading to bilineal inheritance. Sib-pairs with both parents alive are unusual, so identity by descent analysis is rarely feasible. Strategies to reduce bilineal inheritance by identifying sib-pairs with one known nondiabetic parent or with the second sibling having mild subclinical diabetes may be worthwhile. Identification of individuals or pedigrees with an unusual phenotype that suggests a single gene disorder, such as maturity-onset diabetes of the young, will continue to be important, for this allows linkage analysis with markers near candidate genes and exclusion mapping of chromosomal regions using highly polymorphic markers. Population association studies with candidate genes can detect mutations that have a minor role in the majority proportion of diabetic subjects, but large numbers are required and great care must be taken to exclude ethnic group differences between the diabetic and normoglycemic populations. The study of small inbred communities might be helpful because they may have fewer diabetogenic genes than outbred populations, and this would increase the power of sib-pair and population association studies. Direct screening for mutations in candidate genes (with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing) in patients with the appropriate pathophysiological abnormality can be a successful strategy. The identification of well-defined diabetic pedigrees, sib-pairs, and suitable matched diabetic and nondiabetic populations will be key to the discovery of the genes for 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.

Elevated plasma concentrations of beta-cell tropin (ACTH22-39) in diet-treated type II diabetic patients.

beta-Cell tropin, the pituitary peptide ACTH22-39, is a potent insulin secretagogue and stimulates lipogenesis in adipose tissue in rodents. Plasma beta-cell tropin was measured fasting and after glucose infusion (5 mg.kg glucose ideal body weight-1.min0-1 for 90 min) in 10 mild diet-treated non-insulin-dependent (type II) diabetic subjects and 10 control subjects (body mass index) (BMI): 26.4 +/- 3.2 and 24.1 +/- 2.0 kg/m-2, NS, fasting plasma glucose 7.8 +/- 2.7 mM and 4.7 +/- 0.3 mM, respectively). The diabetic subjects had raised fasting plasma beta-cell tropin compared with the normal subjects (geometric mean (1 SD range): 0.49 (0.25-0.96) nM and 0.17 (0.10-0.28) nM, respectively, P = 0.007). In response to the glucose infusion, plasma glucose rose higher in the diabetic subjects (mean +/- 1 SD: 13.7 +/- 3.1 and 9.6 +/- 0.9 mM, P = 0.007) and plasma insulin was impaired in the diabetic compared with the nondiabetic subjects (geometric mean (1 SD range): 14 (8-26) and 34 (18-63), P less than 0.01). beta-Cell tropin concentrations in the diabetic subjects rose to 1.31 (0.74-2.30) nM (P = 0.007), whereas beta-cell tropin did not change in the normal subjects at 0.19 (0.11-0.91) nM. There was no overlap between glucose-stimulated plasma beta-cell tropin in the two groups (P = 0.0002). Pituitary-adrenal function, as assessed by plasma cortisol, did not differ between the two groups when fasting and did not change after the glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative hyperproinsulinemia of NIDDM persists despite the reduction of hyperglycemia with insulin or sulfonylurea therapy.

Subjects with NIDDM have increased plasma proinsulin concentrations, compared with nondiabetic subjects, both in absolute terms and as a proportion of circulating insulin-like molecules. It remains uncertain whether this reflects a primary beta-cell defect in proinsulin processing or is secondary to hyperglycemia. We addressed this question by assessing the effects of reducing hyperglycemia on relative hyperproinsulinemia in subjects with NIDDM. Eight subjects with NIDDM underwent three 8-week periods in a randomized crossover design of therapy with diet alone, sulfonylurea (gliclazide), or insulin (ultralente). The effects on beta-cell peptide concentrations were assessed 1) fasting, 2) in response to hyperglycemic clamping, and 3) in response to an injection of the nonglucose secretogogue arginine and compared with measurements in seven nondiabetic control subjects. Both sulfonylurea and insulin therapy substantially reduced fasting plasma glucose and glycosylated hemoglobin (HbA1e) concentrations, compared with diet therapy alone. The diabetic subjects on diet therapy had relative hyperproinsulinemia, assessed relative to C-peptide concentrations, fasting and in response to hyperglycemic clamping and arginine, compared with control subjects. Neither sulfonylurea nor insulin therapy altered the relative hyperproinsulinemia. Insulin therapy reduced fasting proinsulin concentrations from geometric mean 29.4 (1 SD range, 14.6-59.0) pmol/l on diet therapy to 18.7 (7.3-48.1) pmol/l (P < 0.05). A similar trend was evident with fasting C-peptide concentrations with a reduction from 0.9 (0.6-1.4) nmol/l on diet therapy to 0.6 (0.4-0.9) nmol/l (P = 0.06), so that the relative hyperproinsulinemia, assessed as the ratio of fasting proinsulin to C-peptide, was unchanged by insulin. Similarly, insulin therapy failed to reduce the ratio of proinsulin to C-peptide concentrations in response to a hyperglycemic clamp and in the acute incremental response to arginine. Failure to improve the relative hyperproinsulinemia of NIDDM, despite significant reduction of hyperglycemia with exogenous insulin therapy, supports the hypothesis that relative hyperproinsulinemia in NIDDM is a reflection of a primary beta-cell defect rather than being secondary to hyperglycemia.

Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM.

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans. Its effects on overnight glucose concentrations and the specific phases of insulin response to glucose and nonglucose secretogogues in subjects with NIDDM are not known. We compared the effects of overnight intravenous infusion of GLP-1 (7-36) amide with saline infusion, on overnight plasma concentrations of glucose, insulin, and glucagon in eight subjects with NIDDM. The effects on basal (fasting) beta-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the insulin response to a subsequent bolus of the nonglucose secretogogue, arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimulated beta-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of which was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasma glucose concentrations compared with saline, with mean postabsorptive glucose concentrations (2400-0800) of 5.6 +/- 0.8 and 7.8 +/- 1.4 mmol/l, respectively (P < 0.0002). Basal beta-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% beta (24-85) to 91% beta (55-151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-8-33) to 116 pmol/l (12-438) (P < 0.005), second-phase insulin response to glucose from 136 pmol/l (53-352) to 1,156 pmol/l (357-3,748) (P < 0.0002), and incremental insulin response to arginine from 443 pmol/l (172-1,144) to 811 pmol/l (272-2,417) (P < 0.002). All responses on GLP-1 were not significantly different from nondiabetic control subjects. Reduction of overnight glucose by exogenous insulin did not improve any of the phases of stimulated beta-cell function. Prolonged intravenous infusion of GLP-1 thus significantly lowered overnight glucose concentrations in subjects with NIDDM and improved both basal and stimulated beta-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of hyperglycemia in NIDDM.

Distribution of type II diabetes in nuclear families.

Type II diabetes has a substantial genetic component, but the mode of inheritance and the molecular basis of this inheritance are uncertain. This study documents the familial distribution of the disease in the parents and siblings of a consecutive series of type II diabetic subjects. We studied 66 first-degree relatives of 20 white subjects with type II diabetes and both parents alive. They were tested with a continuous infusion of glucose (5 mg.kg IBW-1.min-1) (n = 49) or FPG and hemoglobin A1c (n = 17). Seven probands had neither parent affected with diabetes or IGT, 10 had one parent affected (6 with diabetes and 4 with IGT), and 3 had both parents affected. The probands with affected and those with unaffected parents were phenotypically similar. These findings indicate that a sizable subgroup of type II diabetic subjects may have neither parent affected with a demonstrable abnormality of glucose tolerance. The assumption of autosomal dominance with complete penetrance is not supported, although it remains possible that a dominant gene of low penetrance may play a role in some pedigrees. Polygenic inheritance would appear likely, and genetic heterogeneity may occur. The inheritance of diabetic traits from phenotypically normal parents needs to be considered in the analysis of genetic linkage with type II diabetes.

Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.

Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.

Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166).

OBJECTIVE: This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal. RESEARCH DESIGN AND METHODS: A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min. RESULTS: The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide. CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.

Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance.

OBJECTIVE-Assessment and follow-up of early renal dysfunction is important in diabetic nephropathy. Plasma creatinine is insensitive for a glomerular filtration rate (GFR) >50 ml/min and creatinine clearance is unwieldy and subject to collection inaccuracies. We aimed to assess the reproducibility, reliability, and accuracy of plasma cystatin C as a measure of GFR ranging from normal to moderate impairment due to type 1 diabetes in the presence of a normal plasma creatinine concentration. RESEARCH DESIGN AND METHODS-A sensitive immunoturbidimetric cystatin C assay was examined in 29 subjects with type 1 diabetes and 11 nondiabetic subjects. Duplicate measurements of the following were collected from each subject, 2 weeks apart: cystatin C, enzymatic plasma creatinine, 24-h creatinine clearance, GFR estimated from plasma creatinine by the Cockcroft-Gault equation, and iohexol clearance as a gold standard. RESULTS-Iohexol clearance ranged from 35 to 132 ml. min(-1). 1.73 m(-2). Plasma cystatin C compared well with the other clinically used tests. The reliability of cystatin C, as assessed by the discriminant ratio, was superior to creatinine clearance (3.4 vs. 1.5, P < 0.001) and the correlation of cystatin C with iohexol clearance (Rs -0.80) was similar to that of creatinine clearance (Rs -0.74) and superior to that of plasma creatinine and the Cockcroft-Gault estimate (Rs -0.54 and 0.66, respectively). Duplicate estimations were used to provide an unbiased equation to convert plasma cystatin C to GFR. CONCLUSIONS-Based on this study, cystatin C is a more reliable measure of GFR than creatinine clearance, is more highly correlated with iohexol clearance than plasma creatinine, and is worthy of further investigation as a clinical measure of GFR in type 1 diabetes.

Changes in amylin and amylin-like peptide concentrations and beta-cell function in response to sulfonylurea or insulin therapy in NIDDM.

OBJECTIVE: Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS: In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS: Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l). CONCLUSIONS: By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone.

No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.

Suicidality, depression, and substance abuse in adolescence.

The authors assessed the occurrence of suicidal ideation, suicide attempts, major depression, and substance abuse in a sample of 424 apparently healthy college students 16-19 years old. Major depression and substance abuse were independent and interactive risk factors for suicidal ideation and for suicide attempts; substance abuse had a particularly deleterious effect on men. A prolonged desire to be dead was a more specific risk factor for a suicide attempt than was a thought of suicide. The authors conclude that suicidal ideation in the presence of major depression and/or substance abuse in older adolescents should call forth greater concern for lethality.

Vulnerable children: parents' perspectives and the use of medical care.

In a study of use of five general pediatric services, 750 parents were interviewed on site about their decisions on how and when to seek medical care for their children. Parents' fears that a particular child was "vulnerable"--ie, uniquely threatened by an episode of illness--was a recurrent concern (reported by 27%), explaining many of their medical visits. Medical record review indicated that in 40%, there was no clinical basis for these parent concerns. One important source of these unwarranted concerns was fear of recurrence of an earlier medical problem, long since resolved. In some families, the role of social and environmental issues in generating a high level of concern was evident. Vulnerable children made more visits per year and made many more of their visits to the emergency room, and their parents more often expressed dissatisfaction with care received. Recognition of reasons underlying parents' sense of the child's special status may do much to allay unnecessary fears and promote more appropriate use of health care facilities.

Controlled clinical trial of pediatric telephone protocols.

A randomized clinical trial of pediatric protocols administered by health assistants demonstrated an alternate method of handling telephone complaints in a large emergency room. The new system advised a higher medical examination rate than the current system in the emergency room probably bacause the current system has deficits with respect to collecting necessary information and making explicit decisions. This higher rate of recommended visits demonstrated in the emergency room was not confirmed in the two pediatric primary-care settings in which the protocol system was also tested. In addition to this use, the telephone protocols may also be useful in training medical and nursing students, in handling telephone complaints similar to a poison control center, in triaging problems in a rural or emergency medical service, and in providing a record of the telephone call.