Biomedical subjects

S Efendic

Publications and source records attributed to S Efendic.

At least 19 recordsLinked to original sources

PubMed2006

Diabetic Goto-Kakizaki rats display pronounced hyperglycemia and longer-lasting cognitive impairments following ischemia induced by cortical compression.

Hyperglycemia has been shown to worsen the outcome of brain ischemia in several animal models but few experimental studies have investigated impairments in cognition induced by ischemic brain lesions in hyperglycemic animals. The Goto-Kakizaki (GK) rat naturally develops type 2 diabetes characterized by mild hyperglycemia and insulin resistance. We hypothesized that GK rats would display more severe cerebral damage due to hyperglycemia-aggravated brain injury and, accordingly, more severe cognitive impairments. In this study, recovery of motor and cognitive functions of GK and healthy Wistar rats was examined following extradural compression (EC) of the sensorimotor cortex. For this purpose, tests of vestibulomotor function (beam-walking) and combined tests of motor function and learning (locomotor activity from day (D) 1 to D5, operant lever-pressing from D14 to D25) were used. EC consistently reduced cerebral blood flow in both strains. Anesthesia-challenge and EC resulted in pronounced hyperglycemia in GK but not in Wistar rats. Lower beam-walking scores, increased locomotor activity, impairments in long-term habituation and learning of operant lever-pressing were more pronounced and observed at later time-points in GK rats. Fluoro-Jade, a marker of irreversible neuronal degeneration, revealed consistent degeneration in the ipsilateral cortex, hippocampus and thalamus at 2, 7 and 14 days post-compression. The amount of degeneration in these structures was considerably higher in GK rats. Thus, GK rats exhibited marked hyperglycemia during EC, as well as longer-lasting behavioral deficits and increased neurodegeneration during recovery. The GK rat is thus an attractive model for neuropathologic and cognitive studies after ischemic brain injury in hyperglycemic rats.

Animals↗

PubMed2006

The impact of family history of diabetes and lifestyle factors on abnormal glucose regulation in middle-aged Swedish men and women.

AIMS/HYPOTHESIS: We investigated associations between abnormal glucose regulation and family history of diabetes, separately and in combination with lifestyle risk factors. SUBJECTS AND METHODS: This cross-sectional study comprised 3,128 men and 4,821 women, aged 35-56 years, half with a family history of diabetes. Oral glucose tolerance testing identified subjects with previously undiagnosed prediabetes (IFG, IGT) and type 2 diabetes. Information on lifestyle factors was obtained by questionnaire. Biological interaction was measured with the synergy index. RESULTS: A family history of diabetes conferred a higher odds ratio (OR) for type 2 diabetes in men (OR=3.1, 95% CI 1.7-5.6) than in women (OR=1.7, 95% CI 1.0-3.0), and the synergy index was 2.8 (95% CI 0.9-9.0), suggesting interaction between a family history of diabetes and sex. For prediabetes and diabetes combined, the synergy index was 1.7 (1.0-2.8). Exposure to only one lifestyle risk factor (obesity, physical inactivity, smoking or low sense of coherence [a psychosocial index]) increased the risk to a similar extent in men and women. Combined exposure to a family history of diabetes and lifestyle-related risk factors had a greater effect on type 2 diabetes than any of these factors alone, especially in men. However, analysis of interaction between a family history of diabetes and the lifestyle factors did not indicate any interaction for diabetes, but did indicate interaction for a family history of diabetes and obesity in women with prediabetes. CONCLUSIONS/INTERPRETATION: Our data suggest a more pronounced effect of a family history of diabetes on the risk of type 2 diabetes in men than in women. While both a family history of diabetes and lifestyle risk factors had effects on type 2 diabetes, irrespective of sex, these effects did not appear to interact.

Adult↗

PubMed2006

Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes.

AIMS/HYPOTHESIS: Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation. MATERIALS AND METHODS: Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT). RESULTS: In the short-term study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p = 0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p = 0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts. CONCLUSIONS/INTERPRETATION: Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.

Animals↗

PubMed2006

Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver.

AIMS/HYPOTHESIS: We used oestrogen receptor-alpha (ERalpha) knockout (ERKO) and receptor-beta (ERbeta) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. METHODS: Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. RESULTS: ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemic-hyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. CONCLUSIONS/INTERPRETATION: We conclude that oestrogens, acting via ERalpha, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.

Adiponectin↗

PubMed2006

Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.

AIM: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM-1 gene polymorphisms on the development of T1D and diabetic nephropathy. METHODS: Five valid single nucleotide polymorphisms (SNPs) were genotyped in 432 T1D patients (196 patients had diabetic nephropathy) and 187 non-diabetic control subjects by using dynamic allele-specific hybridization (DASH) and pyrosequencing. RESULTS: SNPs rs281432(C/G) and rs5498 E469K(A/G) had high heterozygous indexes. They were significantly associated with T1D [P = 0.026, OR = 1.644 (95% CI 1.138-2.376) and P < 0.001, OR = 2.456 (1.588-3.8)]. Frequencies of the C allele in SNP rs281432(C/G) and the A allele in SNP rs5498 E469K(A/G) increased stepwise from non-diabetic control subjects to T1D patients without diabetic nephropathy and T1D patients with diabetic nephropathy. Further analysis for these two SNPs indicated that T1D patients had increased frequency of the common haplotype C-A, in comparison with non-diabetic control subjects (38.1 vs. 32.1%, P = 0.035). CONCLUSION: The present study provided evidence that SNPs rs281432(C/G) and rs5498 E469K(A/G) in the ICAM-1 gene confer susceptibility to the development of T1D and might also be associated with diabetic nephropathy in Swedish Caucasians.

Adult↗

PubMed2005

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years.

AIMS/HYPOTHESIS: Insulin resistance and insulin deficiency are proposed as risk factors for IGT and type 2 diabetes. We assessed the predictive value of initial parameters for the outcome of an OGTT performed 24.3+/-2.9 years later in an unselected healthy non-obese population. METHODS: The K-value of an IVGTT was determined in 267 healthy subjects (mean+/-SD: age 31.0+/-12.0 years, BMI 21.8+/-2.8 kg/m(2)). First-phase insulin response to a glucose infusion test was estimated as an incremental 5- or 10-min (DeltaI5 or DeltaI10) value, and as insulinogenic indices (DeltaI5/DeltaG5 or DeltaI10/DeltaG10) adjusted for insulin sensitivity determined by homeostasis model assessment for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR). RESULTS: At follow-up, six subjects had type 2 diabetes and 47 had IGT; 214 retained normal glucose tolerance. Insulin sensitivity and early (30 min) insulin response decreased with decreasing outcome OGTT. Blood glucose (2 h) at OGTT correlated positively with initial age and BMI, and negatively with DeltaI5/DeltaG5, (DeltaI5/DeltaG5)/HOMA-IR and K-value. In multiple linear regression analysis, (DeltaI5/DeltaG5)/HOMA-IR, DeltaI10, K-value, age, HOMA estimate of insulin secretion, and fasting plasma glucose were significantly associated with 2-h OGTT blood glucose. Similar results were obtained on comparing differences between subjects with normal and decreased (IGT+diabetes) glucose tolerance. CONCLUSIONS/INTERPRETATION: In 267 non-obese healthy subjects, initial K-value and first-phase insulin response to glucose adjusted for insulin sensitivity, but not insulin sensitivity itself, were strong predictors of the outcome of an OGTT performed 25 years later. Thus, in contrast to obese or other high-risk populations, in lean subjects, decreased beta cell function, but not insulin resistance itself, determines future glucose tolerance.

Adolescent↗

PubMed2005

Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study.

AIMS/HYPOTHESIS: Patients with acute myocardial infarction (AMI) but without previously known type 2 diabetes have a high prevalence of undiagnosed IGT and type 2 diabetes. Such perturbations have dismal prognostic implications. The aim of this study was to characterise AMI patients in terms of insulin resistance and beta cell function. METHODS: A total of 168 consecutive AMI patients were classified by means of an OGTT before hospital discharge as having NGT, IGT or type 2 diabetes. The homeostasis model assessment (HOMA-IR) was used to estimate insulin resistance. Beta cell responsiveness was quantified as insulinogenic index (IGI) at 30 min (DeltaI(30)/DeltaG(30)). RESULTS: According to the HOMA-IR, patients with type 2 diabetes were more insulin resistant than those with IGT or NGT (p=0.003). Beta cell responsiveness deteriorated with decreasing glucose tolerance as measured by the IGI (median [quartile 1, quartile 3] in pmol/mmol: NGT, 70.1 [42.7, 101.4]; IGT, 48.7 [34.7, 86.8], type 2 diabetes, 38.1 [25.7, 61.6]; p<0.001). The IGI was significantly related to admission capillary blood glucose (r=-0.218, p=0.010) and to the area under the curve for glucose (r=-0.475, p<0.001). CONCLUSIONS/INTERPRETATION: Glucose abnormalities are very common in patients with AMI but without previously known type 2 diabetes. To a significant extent, this seems to be related to impaired beta cell function and implies that dysglycaemia immediately after an infarction is not a stress epiphenomenon but reflects stable disturbances of glucose regulation preceding the AMI. Early beta cell dysfunction may have important pathophysiological implications and may serve as a future target for treatment strategies.

Case-Control Studies↗

PubMed2005

Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

Aged↗

PubMed2005

Association study between chromosome 10q26.11 and obesity among Swedish men.

OBJECTIVE: Proximal chromosome 10q26 was recently linked to waist/hip ratio in European and African-American families. The objective was to investigate whether genomic variation in chromosome 10q26.11 reflects variation in obesity-related clinical parameters in a Swedish population. DESIGN: Genetic association study of single-nucleotide polymorphisms (SNPs) in chromosome 10q26.11 and obesity-related clinical parameters was performed. Obesity was defined as body mass index (BMI) > or = 30 kg/m2. SUBJECTS: Swedish Caucasians comprising 276 obese and 480 nonobese men, 313 obese and 494 nonobese women, 177 obese and 163 nonobese patients with type 2 diabetes mellitus (T2DM), and 106 obese and 201 nonobese subjects with impaired glucose tolerance (IGT) patients. MEASUREMENTS: Genotypes of 11 SNPs at chromosome 10q26.11, and various obesity-related clinical parameters. RESULTS: Homozygosity of a common haplotype constructed by three SNPs, rs2185937, rs1797 and hCV1402327, covering an interval of 2.7 kb, was suggested to confer an increased risk for obesity of 1.5 among men (P = 0.043). The C allele frequency and homozygous genotype frequency of the rs1797 tended to be higher among obese compared to among nonobese men (P = 0.017 and 0.020, respectively). The distribution of BMI and diastolic blood pressure was higher among those with the C/C genotype (P = 0.022 and 0.0061, respectively). The obese and the nonobese groups were homogeneous over BMI subgroups with regard to rs1797 risk genotype distribution. There was no tendency for association between rs1797 and obesity among neither women nor T2DM nor IGT patients. CONCLUSION: We show support for association between proximal chromosome 10q26.11 and obesity among Swedish men but not women through the analysis of a haplotype encompassing 2.7 kb.

Adolescent↗

PubMed2005

Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men.

The neuropeptide Y (NPY) is a neuropeptide with a role in the regulation of satiety and energy balance of body weight, insulin release, cardiovascular and central endocrine systems. In order to evaluate whether the NPY gene variations contribute to development of type 2 diabetes (T2DM), we have performed a genetic association study for Leu7Pro (T1128 C) polymorphism of the NPY gene in impaired glucose tolerance (IGT) and T2DM. Genotyping experiments for this non-synonymous single nucleotide polymorphism (SNP) in 263 patients with T2DM, 309 subjects with IGT and 469 non-diabetic healthy individuals in Swedish Caucasians were performed by using Dynamic Allele Specific Hybridisation (DASH). We found that the frequencies of the "risk" allele C in the subjects with IGT and the patients with T2DM in Swedish men were 13 % (p = 0.002, OR = 3.70, 1.65 - 8.29 95 % CI) and 10 % (p = 0.007, OR = 4.80, 1.47 - 11.33 95 % CI) respectively, which were significantly higher than the C allele frequency in non-diabetic controls (6 %). Furthermore, we found that the carriers with TC and CC genotypes in the subjects with IGT in Swedish men had significantly higher fasting plasma glucose in comparison with the TT carriers (5.6 +/- 0.7 mmol/l vs. 5.2 +/- 0.7 mmol/l, p = 0.021). The present study thus provides the evidence that Leu7Pro polymorphism in the NPY gene is associated with IGT and T2DM in Swedish men, and indicates that the NPY gene variations contribute to development of T2DM. Questions of gender specificity may be explained by genetic backgrounds, sense of coherence for stress and other factors in environment.

Adult↗

PubMed2004

Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity.

AIMS/HYPOTHESIS: We evaluated the impact of sex and type 2 diabetes heredity on the prevalence and pathogenesis of early abnormalities of glucose homeostasis in subjects participating in the Stockholm Diabetes Prevention Programme. METHODS: A sample of 3,128 men and 4,821 women, of whom approximately half had a family history of type 2 diabetes (FHD) was categorised according to an OGTT: NGT, IFG, IGT, combined glucose intolerance and type 2 diabetes. The homeostasis model assessment was used to determine insulin sensitivity and beta cell function. RESULTS: Prevalence of early abnormalities of glucose metabolism was two to three times higher in subjects with FHD and two to three times higher in men compared to women. Both maternal and paternal heredity of type 2 diabetes were associated with an increased risk of having early abnormalities of glucose metabolism. However, in women with type 2 diabetes heredity on the father's side seems to have less impact on an increased risk of having type 2 diabetes. Both waist circumference and systolic blood pressure were increased in subjects with abnormalities of glucose homeostasis, whereas insulin sensitivity and beta cell function were decreased. Subjects with IFG had more pronounced impairment of beta cell function and insulin sensitivity than subjects with IGT. CONCLUSION/INTERPRETATION: An FHD and male sex increased the prevalence of abnormalities of glucose homeostasis. Subjects with IFG had more pronounced defects of insulin secretion and action than subjects with IGT.

Blood Glucose↗

PubMed2004

Coffee consumption, type 2 diabetes and impaired glucose tolerance in Swedish men and women.

OBJECTIVES: The association between coffee consumption, type 2 diabetes and impaired glucose tolerance was examined. In addition, indicators of insulin sensitivity and beta-cell function according to homeostasis model assessment were studied in relation to coffee consumption. DESIGN: Population-based cross-sectional study. SETTING AND SUBJECTS: The study comprised 7949 healthy Swedish subjects aged 35-56 years residing within five municipalities of Stockholm. An oral glucose tolerance test identified 55 men and 52 women with previously undiagnosed type 2 diabetes and 172 men and 167 women with impaired glucose tolerance. Information about coffee consumption and other factors was obtained by questionnaire. RESULTS: The relative risks (adjusted for potential confounders) of type 2 diabetes and impaired glucose tolerance when drinking >/=5 cups of coffee per day compared with </=2 cups per day in men were 0.45 [95% confidence intervals (CI) 0.22-0.92] and 0.63 (CI: 0.41-0.97), respectively, and in women 0.27 (CI: 0.11-0.66) and 0.47 (CI: 0.29-0.76) respectively. In subjects with type 2 diabetes and impaired glucose tolerance, high coffee consumption (>/=5 cups day(-1)) was inversely associated with insulin resistance. In addition, in those with type 2 diabetes and in women (not in men) with impaired glucose tolerance high coffee consumption was inversely associated with low beta-cell function. In women, but not obviously in men, with normal glucose tolerance, coffee consumption was associated with a reduced risk of insulin resistance. CONCLUSIONS: The results of this study indicated that high consumers of coffee have a reduced risk of type 2 diabetes and impaired glucose tolerance. The beneficial effects may involve both improved insulin sensitivity and enhanced insulin response.

Adult↗

PubMed2004

Abnormal glucose tolerance--a common risk factor in patients with acute myocardial infarction in comparison with population-based controls.

BACKGROUND: A high prevalence of newly detected diabetes and impaired glucose tolerance (abnormal glucose tolerance) was recently reported in patients with acute myocardial infarction. It is important to verify whether this finding is specific for the patients or attributable to the population, from which they were recruited. OBJECTIVE: To verify whether abnormal glucose tolerance is more prevalent in patients than in controls chosen from the same population and to compare metabolic characteristics between the two groups. DESIGN AND SUBJECTS: The metabolic state was assessed in patients (n = 181) admitted with acute myocardial infarction and no history of diabetes before discharge and after 3 months. Sex- and age-matched controls (n = 185) without previously known diabetes or cardiovascular disease except hypertension were recruited from the general population. MAIN OUTCOME MEASURES: Oral glucose tolerance test, glucosylated haemoglobin A1c (HbA1c), insulin, proinsulin, lipid profile, fibrinolytic function and inflammatory markers. RESULTS: Abnormal glucose tolerance was more common (number/all classified) in patients at discharge 113/168 (67%) and after 3 months 95/145 (66%) than in controls 65/185 (35%) (P < 0.001). Dyslipidaemia (70% vs. 29%; P < 0.001) and previously treated hypertension (32% vs. 18%; P = 0.028) were more frequent amongst patients whilst obesity (18% vs. 24%) did not differ significantly. Blood glucose, HbA1c, proinsulin, proinsulin/insulin ratio, triglycerides, insulin resistance (by HOMA) and fibrinogen were consistently higher in patients than controls (P < 0.01). CONCLUSIONS: Abnormal glucose tolerance was almost twice as common amongst patients with acute myocardial infarction as in matched controls. Impaired glycaemic control accompanied by insulin resistance, dyslipidaemia, hypertension, together with increased plasma fibrinogen and proinsulin levels were main features characterizing patients.

Acute Disease↗

PubMed2003

Identification of the bioactive peptide PEC-60 in brain.

PEC-60 is a 60-residue peptide originally isolated from pig intestine. It inhibits glucose-induced insulin secretion from perfused pancreas in a hormonal manner and also has biological activity in the immune system. PEC-60-like immunoreactive material has been reported in catecholamine neurons of the central and peripheral nervous systems, but the peptide has not been identified from that material. We have now isolated PEC-60 from pig and rat brains with a method that combines column purification procedures with the specificity of a radioimmunoassay and the sensitivity of mass spectrometry to directly identify the peptide. The results show that PEC-60, like many other peptides, is expressed in the gastrointestinal tract and the central nervous system. The specific regional brain distribution and interaction with classical neurotransmitters raise the possibility that PEC-60 may play a role in the central nervous system disorders involving dopamine dysregulation.

Animals↗

PubMed2002

Hyperproinsulinemia and proinsulin-to-insulin ratios in Swedish middle-aged men: association with glycemia and insulin resistance but not with family history of diabetes.

Elevated proinsulin and proinsulin/insulin ratios are features of abnormal beta-cell function in type 2 diabetes. The participation of genetic factors is disputed. The authors wished to investigate relations between family history of diabetes on one hand and proinsulin as well as proinsulin/immunoreactive insulin ratios on the other. A large, population-based sample of Swedish men aged 35-54 years in 1992 was studied. Subjects without known diabetes were selected either to have a strong family history of diabetes (n = 1,619) or no history of the disease (n = 1,495). An oral glucose tolerance test detected 172 subjects with impaired glucose tolerance and 55 subjects with previously unknown diabetes according to World Health Organization 1985 criteria. In multiple regression analysis, fasting levels of proinsulin and proinsulin/insulin ratios were positively associated both with the 2-hour glucose level (as a continuous variable) and with obesity, whereas a negative association was found with birth weight. No association was found with family history of diabetes or with chronologic age. These findings indicate that elevated proinsulin and proinsulin/insulin ratios are secondary to increased demands on beta-cell secretion induced by hyperglycemia and insulin resistance with no discernible influence of family history of diabetes.

Adult↗

PubMed2002

A rapid increase in beta-cell function by multiple insulin injections in type 2 diabetic patients is not further enhanced by prolonging treatment.

OBJECTIVE: Intensive insulin treatment in type 2 diabetes can improve beta-cell function. It is not known which duration of treatment achieves maximal improvement. We addressed this question in type 2 diabetic patients who displayed features of 'secondary failure'. RESEARCH DESIGN AND METHOD: Ten patients were randomized to multiple insulin injection (MI) therapy for 9 weeks. Another 10 patients started with bedtime insulin (BTI) and continued their peroral medication. Following 9 weeks of treatment, patients on MI switched to BTI and glibenclamide. RESULTS: Three days of MI led to a decrease in fasting proinsulin/insulin ratio, 0.43 +/- 0.20 vs. 0.29 +/- 0.11, P=0.01 and an increase in glucagon-stimulated C-peptide over baseline, 0.77 +/- 0.43 vs. 1.28 +/- 0.44 nmol L-1, P 0.02. Nine weeks of MI treatment successively decreased fasting and nonfasting blood glucose in parallel with increasing insulin dosage. Initial improvements in secretion parameters were upheld but not further enhanced, the 9 week proinsulin/insulin ratio being 99 +/- 23% and that of glucagon-stimulated C-peptide being 95 +/- 24% of the values obtained after 3 days of treatment. Eight weeks after termination of MI there persisted a total weight gain that tended to be larger than after continuous peroral medication with BTI. CONCLUSION: Improvement of insulin secretion by intensive insulin treatment is rapidly gained with no further effect obtained after a longer treatment period. This finding, as well as undesirable effects of MI on body weight, argues against prolonged MI treatment as a prelude to other therapeutic regimens in type 2 diabetic patients.

Blood Glucose↗

PubMed2001

The imidazoline RX871024 stimulates insulin secretion in pancreatic beta-cells from mice deficient in K(ATP) channel function.

Effects of the imidazoline compound RX871024 on cytosolic free Ca(2+) concentration ([Ca(2+)]i) and insulin secretion in pancreatic beta-cells from SUR1 deficient mice have been studied. In beta-cells from wild-type mice RX871024 increased [Ca(2+)]i by blocking ATP-dependent K(+)-current (K(ATP)) and inducing membrane depolarization. In beta-cells lacking a component of the K(ATP)-channel, SUR1 subunit, RX871024 failed to increase [Ca(2+)]i. However, insulin secretion in these cells was strongly stimulated by the imidazoline. Thus, a major component of the insulinotropic activity of RX871024 is stimulation of insulin exocytosis independently from changes in K(ATP)-current and [Ca(2+)]i. This means that effects of RX871024 on insulin exocytosis are partly mediated by interaction with proteins distinct from those composing the K(ATP)-channel.

Animals↗

PubMed2001

Ser(13)-phosphorylated PYY from porcine intestine with a potent biological activity.

We have isolated a posttranslationally modified form of peptide YY (PYY) from porcine intestine and shown by MALDI-TOF and electrospray tandem mass spectrometry that it is phosphorylated at Ser(13). Phospho-PYY exhibits high affinity for binding to neuropeptide Y (NPY) receptors Y1, Y2 and Y5. The IC(50) values with the Y1, Y2, and Y5 receptor subtypes were for NPY 2.4, 3.1, and 3.3 nM, for PYY 2.3, 0.94, and 3.2 nM, and for phospho-PYY 4.6, 2.2, and 5.5 nM, respectively. Phospho-PYY potently inhibits forskolin-stimulated cAMP accumulation in SK-N-MC cells with an IC(50) value of 0.5 nM compared to 0.15 nM for non-phosphorylated PYY. The finding of phosphorylation of PYY is unusual among hormonal peptides, and emphasizes the importance of direct protein analysis of gene products.

Amino Acid Sequence↗