Glucagon-like peptide (GLP)-1 and leptin concentrations in obese patients with Type 2 diabetes mellitus.

AIMS: To assess differences in circulating leptin and glucagon-like peptide (GLP)-1 concentrations before and after an oral glucose load, in euglycaemic and isoinsulinaemic conditions, between obese patients with and without Type 2 diabetes mellitus. METHODS: Ten male obese (body mass index (BMI) > 30 kg/m2) patients with Type 2 diabetes and 20 matched non-diabetic subjects were studied. Leptin, GLP-1(7-36)amide and GLP-1(7-37) concentrations were measured 0, 30, 60, and 90 min after a 50-g oral glucose load administered 90 min after the beginning of a euglycaemic hyperinsulinaemic clamp. RESULTS: GLP-1(7-36)amide concentrations before the glucose load were significantly lower in diabetic patients than in controls (median (quartiles): 50.5 (44.7-53.2) vs. 128.7(100-172.5) pg/ml; P < 0.01), while no difference was observed in baseline GLP-1(7-37). In non-diabetic subjects, GLP-1(7-36)amide and GLP-1(7-37) concentrations increased significantly after the oral glucose load, while no glucose-induced increase in GLP-1 concentration was observed in diabetic patients. GLP-1(7-36)amide at 30, 60, and 90 min, and GLP-1(7-37) at 30 min, of the glucose challenge, were significantly lower in diabetic patients. Leptin concentrations were not significantly different in diabetic patients when compared to non-diabetic subjects, and they did not change after the oral glucose load. DISCUSSION: Leptin concentrations are not significantly modified in obese Type 2 diabetic patients. GLP-1(7-36)amide baseline concentrations are reduced in Type 2 diabetes; moreover, diabetic subjects show an impaired response of GLP-1 to oral glucose in euglycaemic, isoinsulinaemic conditions. This impairment, which is not the result of differences in glycaemia or insulinaemia during assessment, could contribute to the pathogenesis of hyperglycaemia in Type 2 diabetes mellitus.     

Are the binding and degradation of low density lipoprotein altered in type 2 (non-insulin-dependent) diabetes mellitus?

Summary Studies in vitro have shown that glycosylation of low density lipoprotein (LDL) will decrease its ability to bind to its receptor. We have evaluated the possibility that such an event might occur in vivo in diabetes by comparing the binding and degradation by normal fibroblasts and mouse peritoneal macrophages of LDL obtained from normal control subjects and patients with Type 2 (non-insulin-dependent) diabetes mellitus. When compared with control subjects, Type 2 diabetic patients had elevated fasting glucose (increased by 160%), haemoglobin A_1c (increased by 75%), triglyceride (increased by 550%), and cholesterol (increased by 48%) levels. LDL from Type 2 diabetic patients displayed populations of particles with more heterogeneous hydrated densities than LDL from control subjects, with enrichment in the triglyceride content of the lighter population. ¹²⁵I-LDL from normal and Type 2 diabetic subjects bound to fibroblasts with similar binding affinities and binding capacities. The kinetics of degradation of LDL from normal and Type 2 diabetic subjects by fibroblasts were also similar. Furthermore, all populations of LDL particles from Type 2 diabetic patients were bound and degraded by normal fibroblasts in identical fashions. In addition, ¹²⁵I-LDL from normal and Type 2 diabetic subjects were not bound or degraded by mouse peritoneal macrophages. It is concluded that the LDL of patients with Type 2 diabetes with moderate hyperglycaemia are not modified sufficiently to alter their normal binding and degradation by human fibroblasts or to cause their uptake by mouse peritoneal macrophages.     

Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects

Summary The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.     

Acute hyperglycaemia causes elevation in plasma atrial natriuretic peptide concentrations in Type 1 diabetes mellitus.

AIMS: To examine the effect of acute hyperglycaemia on atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations in Type 1 diabetes. METHODS: The study was two limb, randomized, and single-blind. Eight Type 1 diabetes subjects were clamped at euglycaemia by intravenous infusion of insulin. When euglycaemia was established, the insulin infusion rate was left unaltered for the remainder of the protocol, and an intravenous infusion of either 500 ml 0.9% saline or 500 ml 10% dextrose was administered over 1 h. Blood was collected for estimation of plasma glucose, ANP and BNP concentrations at 30 min intervals for 2 h from the start of the infusion period. One week later, each subject received the alternate infusion. Results are expressed as mean +/- standard deviation, and were analysed by ANOVA. RESULTS: Baseline plasma glucose (P = 0.8), ANP (P = 0.8) and BNP (P = 0.8) concentrations were similar on the study days. Plasma glucose rose with dextrose (6.1 + 0.5-15.1 + 2.8 mmol/l, P = 0.9). Plasma ANP concentrations were unaltered by saline infusion (76.5 +/- 14.7-77.7 +/- 15.2 pg/ml, P = 0.9), but increased with dextrose infusion (79 +/- 14-134 +/- 17.1 pg/ml, P < 0.0001), and were higher with dextrose than saline infusion (P < 0.0001). Plasma concentrations of BNP were not significantly altered by infusion of either dextrose (5.1 +/- 3.9-9.3 +/- 5.4 pg/ml, P = 0.63) or saline (4.3 +/- 3.5-6 +/- 5.2 pg/ml, P = 0.84). CONCLUSIONS: Plasma concentrations of ANP, but not BNP, rise in response to acute hyperglycaemia in Type 1 diabetes.     

C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor

Monocyte scavenger receptor, CD36 has been implicated in the pathogenesis of atherosclerosis as a major oxidised LDL receptor mediating lipid accumulation and foam cell formation. Previously, we found that treatment of monocyte cultures with the carboxyl terminal fragment of alpha1-antitrypsin (C-36) increases lipid binding and uptake, induces LDL receptor mRNA and CD36 receptor protein expression, and also significantly increases production of pro-inflammatory molecules. To assess the role of the CD36 receptor in proatherogenic monocyte activation by the C-36 fragment, we tested whether specific anti-CD36 receptor antibodies would block the effects of C-36 on monocyte activation. We find that pre-incubation of cells with anti-LDL and anti-CD36 receptor antibodies (10 microg/ml) blocks binding of 125I-C-36 by about 50%. Similarly, cells pre-incubated with oxidised LDL or native LDL at concentrations from 2.5 to 10 microg/ml showed a loss of 125I-C-36 binding (up to 49 and 57%) and uptake (up to 47 and 59.8%), respectively. In parallel experiments, monocytes were first incubated for 1 or 6 h with anti-CD36 antibodies (10 microg/ml) prior to adding C-36 peptide. Anti-CD36 antibodies suppressed C-36-induced production of gelatinase B, monocyte chemoattractant protein-1, interleukin-6 and cellular oxygen consumption to control levels, whereas levels of TNFalpha were unaffected. In contrast, saturation of LDL receptors with excess of anti-LDL (20 microg/ml) significantly inhibited C-36 induced TNFalpha levels. Results indicate that the C-36 peptide binds to both LDL and CD36 scavenger receptors which involves selective upregulation of pro-inflammatory molecules and activation of the respiratory burst in human monocytes. This also supports important roles for CD36 and LDL receptors in atherogenesis and suggests that blockade of CD36 receptor can be protective in pro-inflammatory activation of human monocytes.     

The effect of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus.

AIMS: To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus. METHODS: Two separate studies, each involving eight adults with uncomplicated Type 1 diabetes, were performed: one in the fasted state (A) and the other after a nutrient preload (B). In both studies, perceptions of appetite (hunger and fullness) and food intake at a buffet meal were evaluated during euglycaemia (blood glucose, approximately 6 mmol/l) and hyperglycaemia (blood glucose, approximately 14 mmol/l). Both experiments were randomized and single-blind. In study A, appetite was assessed in the fasted state for 90 min before the buffet meal. In study B, a nutrient 'preload' of Ensure and milk containing 13C-octanoic acid was consumed 90 min before the meal. Gastric emptying of the preload was quantified with a radioisotopic breath test technique. RESULTS: There was no significant difference in plasma insulin concentrations between euglycaemia and hyperglycaemia in either study. In study A, there were no differences in hunger, fullness or energy intake between the two treatment days. In study B, subjects were slightly less hungry between the preload and buffet meal during hyperglycaemia than euglycaemia (P = 0.04), and tended to have slower gastric emptying during hyperglycaemia (emptying coefficient, 3.89 +/- 0.16 vs. 3.57 +/- 0.21; P = 0.052), but there was no difference in food intake between hyperglycaemia and euglycaemia. CONCLUSIONS: Acute hyperglycaemia suppresses hunger after a nutrient preload, but not in the fasted state, in patients with uncomplicated Type 1 diabetes. This effect is small and not associated with changes in food intake.     

Relation between glycaemic control,hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes

Aims/hypothesis: Increased plasma concentrations of circulating adhesion molecules in patients with Type II (non-insulin-dependent) diabetes mellitus could be associated with the increased cardiovascular risk in these patients. However, it is controversial whether increased adhesion molecule plasma concentrations are primarily related to hyperglycaemia or to hyperinsulinaemia. Methods: We evaluated the plasma concentrations of soluble E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) at baseline and during euglycaemic hyperinsulinaemic clamp in three different groups without additional cardiovascular risk factors: group A (control group), 28 healthy volunteers with normal glucose tolerance; group B, 24 subjects with fasting hyperinsulinaemia, normal fasting glucose but impaired glucose tolerance; group C, 32 patients with Type II diabetes, fasting hyperinsulinaemia and chronic hyperglycaemia. Results: Plasma soluble E-selectin, ICAM-1, and VCAM-1 concentrations were higher (p < 0.05) in patients with Type II diabetes (group C) compared with the other groups. The adhesion molecule concentrations correlate with the fasting plasma glucose (r = 0.59, p < 0.001), the 2-h OGTT plasma glucose (r = 0.70, p < 0.01), and the HbA_{1 c} value (r = 0.61, p < 0.05). The E-selectin but not the ICAM-1 and VCAM-1 plasma concentrations correlated with the fasting insulin concentrations (r = 0.62, p < 0.05) or the whole body glucose uptake (r = 0.59, p < 0.05) in the clamp. The hyperinsulinaemia during the euglycaemic hyperinsulinaemic clamp had no significant effect on the plasma concentrations of E-selectin, ICAM-1, and VCAM-1 in all three groups. Conclusion/interpretation: Our results suggest that increased E-selectin concentrations are related to hyperglycaemia, hyperinsulinaemia and insulin resistance, whereas increased ICAM-1 and VCAM-1 plasma concentrations in patients with Type II diabetes are rather related to hyperglycaemia than to hyperinsulinaemia or insulin resistance. [Diabetologia (2002) 45: 210–216] Received: 13 August 2001 and in revised form: 1 October 2001     

罗格列酮与胰岛素治疗对2型糖尿病患者胰岛β细胞第一时相分泌功能的影响

目的罗格列酮（RGZ）与胰岛素治疗对2型糖尿病（T2DM）患者胰岛功能的影响。方法FPG）11．1mmol／L的患者随机分为胰岛素治疗（Ins）组和胰岛素＋罗格列酮治疗（Ins＋RGZ）组,两组年龄、病程、BMI均无统计学差异。血糖达标后再维持治疗3个月。治疗前后均作静脉糖耐量试验（IVGTT）,比较两组糖代谢和胰岛功能的变化。结果治疗后的FPG、2hPG、HbA1c、静脉葡萄糖曲线下面积（AUC-G0～60）均显著下降,HOMA—B改善（P〈0．01或P〈0．05）,两组间无统计学差异。两组IVGTT10min内胰岛素释放曲线下面积／60min内胰岛素释放曲线下面积（AUC-I0～10／AUC-I0～60）分别增加10％和12％（P=0．085,0．05）。Ins＋RGZ组I2、I5、I10及FC-P显著提高,Ins组增高无统计学意义。逐步回归分析显示,治疗后FPG和2hPG下降与负荷后胰岛素增值和血糖增值比值呈正相关（r=0．593,P=0．000;r=0．548,P=0．001）,表明治疗后胰岛素处理葡萄糖能力与血糖控制程度呈正相关。结论罗格列酮（而不是胰岛素）能恢复第一时相胰岛素分泌。T2DM患者早期联用RGZ,有利于保护胰岛β细胞功能。     

Inter-relationships between DNA damage, ascorbic acid and glycaemic control in Type 2 diabetes mellitus.

AIMS: The onset of complications in Type 2 diabetes mellitus (DM) patients cannot be predicted in individuals. Evidence suggests a link between complications and hyperglycaemia, oxidative stress and antioxidants, but causality is unclear. This study investigated baseline (entry) fasting plasma ascorbic acid, lymphocytic DNA damage and glycaemic control in Type 2 DM as part of a long-term study, the aim of which is to explore a biomarker profiling approach to identify and improve outcome in high-risk subjects. METHODS: A cross-sectional study, in which DNA damage, glycated haemoglobin (HbA(1c)), fasting plasma glucose (FPG) and ascorbic acid (AA) were measured on fasting blood samples collected from 427 Type 2 DM subjects. RESULTS: DNA damage was significantly (P < 0.0001) and directly correlated to both FPG (r = 0.540) and HbA(1c) (r = 0.282), and was significantly (P < 0.0001), independently and inversely correlated to plasma AA (r = -0.449). In those subjects with both poor glycaemic control and low AA (< 48 microm, the overall mean value for the study group), DNA damage was significantly (P < 0.005) higher compared with those subjects with a similar degree of hyperglycaemia but with AA above the mean. CONCLUSIONS: The novel finding of a significant inverse relationship between plasma AA and DNA damage in Type 2 DM indicates that poorly controlled diabetic subjects might benefit from increased dietary vitamin C. The data also have important implications for biomarker profiling to identify those subjects who might benefit most from intensive therapy. Longer-term follow-up is underway.     

A prospective study of Type 2 diabetes and depressive symptoms in the elderly: the Rancho Bernardo Study.

AIMS: The association between Type 2 diabetes and depressive symptoms was examined prospectively to assess possible causal relationships between the two diseases. METHODS: A cohort of 971 men and women aged 50 and older from the adult population of Rancho Bernardo, California had an oral glucose tolerance test and completed the Beck Depression Inventory (BDI) at two clinic visits, 1984-87 and 1992-96. RESULTS: Depressive symptoms at baseline were associated with higher follow-up levels of non-fasting plasma glucose (P = 0.001) and an increased risk of developing Type 2 diabetes [odds ratio (OR) = 2.50; 95% confidence interval (CI) = 1.29-4.87], independent of sex, age, exercise and body mass index. Conversely, baseline non-fasting plasma glucose was not significantly associated with follow-up depressive symptoms and Type 2 diabetes at baseline was not significantly associated with the onset of BDI scores > or = 11 by the second visit (OR = 0.73; 95% CI = 0.41-1.30). CONCLUSIONS: Depressed mood is more likely to be a risk factor for Type 2 diabetes in older adults than the reverse.     

Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus.

AIMS: Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose-responsive gene in pancreatic B-cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21-1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM. METHODS: The frequency distribution of a 3' UTR single nucleotide polymorphism (SNP) in TXNIP was investigated in subjects with normal glucose tolerance (NGT; n = 379), impaired glucose tolerance (IGT; n = 228) and Type 2 DM (n = 230). Metabolic data were used to determine the effect of this SNP on parameters associated with lipid and glucose metabolism. RESULTS: The frequency of the TXNIP variation did not differ between groups, but within the group of diabetic subjects, carriers of the TXNIP-T variant had 1.6-fold higher triglyceride concentrations (P = 0.015; n = 136) and a 5.5-mmHg higher diastolic blood pressure (P = 0.02; n = 212) than homozygous carriers of the common C-allele, whereas in non-diabetic subjects fasting glucose was 0.26 mmol/l lower (P = 0.002; n = 478) in carriers of the T-allele. Moreover, a significant interaction between plasma glucose concentrations and TXNIP polymorphism on plasma triglycerides was observed (P = 0.012; n = 544). CONCLUSION: This is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia.     

Associations of LDL size with in vitro oxidizability and plasma levels of in vivo oxidized LDL in Type 2 diabetic patients.

AIMS: Oxidative modification of low-density lipoprotein (LDL) is believed to be a key step in the genesis of atherosclerotic lesions. The presence of small, dense LDL is associated with accelerated atherosclerosis and is common in diabetic patients. The aim of this study was to investigate the relationship of in vitro LDL oxidizability and circulating in vivo oxidized LDL with LDL particle size in Type 2 diabetic patients and healthy control subjects. SUBJECTS AND METHODS: The study group consisted of 58 elderly well controlled Type 2 diabetic patients and 58 control subjects with normal glucose metabolism. LDL particle size was measured by high-performance gel-filtration chromatography. In vitro oxidizability of LDL was measured by monitoring conjugated diene formation and plasma levels of circulating oxidized LDL were determined by ELISA. RESULTS: In vitro susceptibility of LDL to oxidation was not related to plasma levels of in vivo oxidized LDL, nor to LDL particle size. In the diabetic patients, but not in the control group, an inverse relation between LDL size and in vivo oxidized LDL was observed (r=-0.35, P=0.007). This relation was strengthened after controlling for LDL-cholesterol concentration (r=-0.52, P<0.001). CONCLUSIONS: In agreement with the view that small, dense LDL accelerates atherosclerosis, an inverse relationship was observed between LDL size and circulating in vivo oxidized LDL in Type 2 diabetic patients. Our results also suggest that in vitro susceptibility to oxidation is not a suitable surrogate measure for in vivo LDL oxidation.     

Effects of eicosapentaenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with Type 2 diabetes mellitus

We compared the levels of microparticles, platelet activation markers, soluble cell adhesion molecules, soluble selectins, and antioxidized low-density lipoprotein (anti-Ox LDL) antibody between patients with hyperlipidemia and control subjects. Binding of anti-glycoprotein (GP) IIb/IIIa and anti-GPIb monoclonal antibodies to platelets did not differ significantly between the hyperlipidemic patients and controls. However, expression of activation markers (CD62P, CD63, PAC-1, and annexin V) by platelets was higher in the hyperlipidemic patients with Type 2 diabetes. The levels of platelet-derived microparticles (PDMPs) and monocyte-derived microparticles (MDMPs) were significantly different in hyperlipidemic patients with Type 2 diabetes and controls. Soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), and anti-Ox LDL antibody also showed higher levels in the hyperlipidemic patients with Type 2 diabetes. After treatment with eicosapentaenoic acid (EPA), the levels of CD62P, CD63, annexin V, PDMPs, and MDMPs, sE-selectin, and oxidized LDL antibody were reduced significantly. Triglyceride (TG) and total cholesterol levels were also decreased. Anti-Ox LDL antibodies and MDMPs were correlated positively with platelet CD62P (plt-CD62P) levels. These findings suggest that in hyperlipidemic patients with Type 2 diabetes, EPA may prevent complications caused by oxidized LDL, E-selectin, and activated platelets or monocytes.     

Polymorphism Ncol in tumor necrosis factor B is associated with fasting glycemia and lipid parameters in healthy non-obese caucasian subjects

BACKGROUND: The study was designed to investigate the associations among polymorphisms TNF-B Ncol and TNF-alpha -308G/A, plasma TNF-alpha levels and metabolic and anthropometric parameters related to insulin sensitivity in a set of 113 Caucasian subjects undergoing oral glucose tolerance test (oGTT). METHODS: Genotypes were detected by PCR; BMI, WHR, glycemia during oGTT, fasting immunoreactive insulin, fasting C-peptide, HbA(1c), total cholesterol, triglycerides, HDL, LDL and plasma TNF-alpha levels were measured in each subject. RESULTS: Type 2 diabetes was diagnosed in 10 subjects, impaired glucose tolerance (IGT) in 41, normal glucose tolerance (NGT) in 62. Significant differences among genotypes of the TNF-B Ncol were observed for FPG (P=0.0063), LDL (P=0.0179) and marginally for total cholesterol (P=0.0763) in NGT group. After the classification of NGT subjects into obese and non-obese according to BMI, associations of TNF-B Ncol with FPG, LDL and cholesterol were proved in non-obese subgroup only. TNF-alpha -308G/A polymorphism was not associated with any of the parameters studied. TNF-alpha levels did not revealed difference among NGT, IGT and DM groups or genotype-dependent differences. CONCLUSIONS: Our results indicate significant association of the TNF-B Ncol polymorphism with FPG, LDL and total cholesterol in normoglycemic non-obese Caucasian subjects. This polymorphism could be involved in genetic modulation of glucose and lipid homeostasis and regulation of insulin sensitivity already in healthy state. Disturbances of this regulation could be component of pathogenesis of type 2 diabetes mellitus.     

Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitus.

AIMS: To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus. METHODS: In eight patients with Type 1, and 10 patients with Type 2 diabetes anorectal motility and sensation were evaluated on separate days while the blood glucose concentration was stabilized at either 5 mmol/l or 12 mmol/l using a glucose clamp technique. Eight healthy subjects were studied under euglycaemic conditions. Anorectal motor and sensory function was evaluated using a sleeve/sidehole catheter, incorporating a barostat bag. RESULTS: In diabetic subjects hyperglycaemia was associated with reductions in maximal (P<0.05) and plateau (P<0.05) anal squeeze pressures and the rectal pressure/volume relationship (compliance) during barostat distension (P<0.01). Hyperglycaemia had no effect on the perception of rectal distension. Apart from a reduction in rectal compliance (P<0.01) and a trend (P=0.06) for an increased number of spontaneous anal sphincter relaxations, there were no differences between the patients studied during euglycaemia when compared with healthy subjects. CONCLUSIONS: In patients with diabetes, acute hyperglycaemia inhibits external anal sphincter function and decreases rectal compliance, potentially increasing the risk of faecal incontinence.     

Pancreatic B-cell function is altered by oxidative stress induced by acute hyperglycaemia.

AIMS: Type 2 diabetes is preceded by a symptom-free period of impaired glucose tolerance (IGT). Pancreatic B-cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B-cell function changes during acute hyperglycaemia induced by oral glucose loading. METHODS: We calculated the insulinogenic index (I.I.) as an indicator of pancreatic B-cell function and measured serum levels of thioredoxin, a marker of cellular redox state, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, during a 75-g oral glucose tolerance test (OGTT) in 45 subjects [24 patients with normal glucose tolerance (NGT), 14 with IGT and seven with Type 2 diabetes]. RESULTS: Thioredoxin levels decreased after glucose loading [66.1 +/- 23.7, *59.3 +/- 22.4, *49.3 +/- 21.2 and *37.7 +/- 18.0 ng/ml, fasting (0 min) and at 30, 60 and 120 min, respectively; *P < 0.001 vs. fasting]. In contrast, concentrations of 8-OHdG peaked at 30 min and then gradually decreased (0.402 +/- 0.123, *0.440 +/- 0.120, 0.362 +/- 0.119 and 0.355 +/- 0.131 ng/ml, *P < 0.05 vs. fasting, P < 0.01 vs. 30 min). The insulinogenic index correlated with the change in thioredoxin levels (r = 0.34, P < 0.05). However, there was no relationship with the change in 8-OHdG levels from 0 to 30 min. CONCLUSIONS: Hyperglycaemia in response to oral glucose impairs pancreatic B-cell function with decreasing thioredoxin levels. The augmented oxidative stress induced by hyperglycaemia may affect the cellular redox state. These findings strongly suggest that repeated postprandial hyperglycaemia may play an important role in the development and progression of diabetes mellitus.     

Effects of cardiac rehabilitation on exercise capacity in Type 2 diabetic patients with coronary artery disease.

AIM: To determine whether Type 2 diabetic patients with coronary disease can obtain, after cardiac rehabilitation, a similar benefit on exercise capacity to non-diabetic coronary individuals. RESEARCH DESIGN AND METHODS: Fifty-nine Type 2 diabetic patients and 36 age-matched non-diabetic patients were enrolled in a 2-month cardiac rehabilitation programme, after an acute coronary event. At the beginning and at the end of the cardiac rehabilitation programme, each subject underwent a cardiopulmonary exercise test to assess exercise capacity as measured by peak workload, duration of test, maximal heart rate, peak VO2 and anaerobic threshold. The two groups of patients were not different in age, sex ratio, type of coronary event or left ventricular ejection fraction. RESULTS: The baseline exercise capacity parameters were not different between diabetic and non-diabetic subjects. After cardiac rehabilitation, improvement of exercise capacity was significantly less in patients with diabetes compared with those without diabetes: peak workload (19% vs. 29%, P = 0.022), peak VO2 (13% vs. 30%, P = 0.002), anaerobic threshold (12% vs. 31%, P = 0.017). In the diabetic patients, a significant inverse relation between fasting blood glucose and change in peak VO2 was observed on both univariate (r = -0.40, P = 0.002) and multivariate (P = 0.001) analyses. CONCLUSIONS: The benefit of cardiac rehabilitation, after an acute ischaemic heart event, in exercise capacity is significantly lower in Type 2 diabetic patients. The response to cardiac rehabilitation in those with diabetes appears to be influenced by blood glucose levels.     

Synergism between mutant HNF1A and the metabolic syndrome in Oji-Cree Type 2 diabetes.

AIMS: To determine the prevalence of the metabolic syndrome in the Sandy Lake Oji-Cree and to examine its interaction with HNF1A in association with impaired glucose tolerance and Type 2 diabetes. METHODS: Using data collected from the Sandy Lake Health and Diabetes Project (1993-1995), the presence or absence of the metabolic syndrome was determined in 515 Oji-Cree subjects, > or = 18 years of age. In the original study, fasting plasma analytes were measured, a 75-g oral glucose tolerance test was administered, and subjects were genotyped for HNF1A G319S. RESULTS: The unadjusted prevalence of the metabolic syndrome in the Oji-Cree adults was 29.9%. The adjusted odds ratio (OR) and 95% confidence interval for Type 2 diabetes among subjects who carried the HNF1A G319S mutation and had the modified metabolic syndrome (excluding hyperglycaemia) was 20.3 (6.94, 59.6). Adjusted ORs for Type 2 diabetes for subjects with either the HNF1A G319S mutation alone or the modified metabolic syndrome alone were 5.56 (2.85, 10.9) and 4.84 (2.53, 9.27), respectively. The risk of having impaired glucose tolerance was not influenced by the presence of either factor. CONCLUSIONS: The risk of Type 2 diabetes was similar (approximately five-fold increased) for subjects with either the presence of the modified metabolic syndrome or the private HNF1A G319S mutation. Interestingly, when present in combination, the two independent risk factors appeared to act synergistically to confer an even greater increased risk of Type 2 diabetes.     

Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulation

Type 2 diabetes is a common disorder with high risk of macrovascular and microvascular complications. These complications are largely driven by hyperglycaemia, dyslipidaemia and hypertension, for which aggressive treatment is thus warranted. Achieving and maintaining control of all three risk factors is especially difficult, however, and new therapeutic approaches could be useful. Bile acids have a well-established and important role in cholesterol homeostasis. Normally, their levels are maintained primarily by ileal reabsorption and enterohepatic recycling. Bile acid sequestrants bind bile acids in the intestine, reduce this recycling and deplete the bile acid pool, thereby stimulating use of hepatic cholesterol for bile acid synthesis, which leads to accelerated removal of LDL from the plasma and a decrease in LDL-cholesterol levels. Interestingly, recent evidence suggests that bile acid sequestrants can lower glucose levels to a clinically meaningful degree. This review presents this evidence and the possible mechanisms by which these glucose-lowering effects occur and discusses the apparently unique ability of bile acid sequestrants among lipid-lowering agents to significantly improve two cardiovascular risk factors, hyperglycaemia and dyslipidaemia. There is renewed interest in the use of bile acid sequestrants in individuals with type 2 diabetes, most of whom would benefit from additional reductions in both LDL-cholesterol and glycaemia.     

Low acute insulin response to intravenous glucose. A sensitive but non-specific marker of early stages of Type 1 (insulin-dependent) diabetes

Summary Preventive treatment of Type 1 (insulin-dependent) diabetes presupposes early and accurate diagnosis of prediabetic states. The low acute insulin response to intravenous glucose has been proposed as a marker of both pre-Type 1 and pre-Type 2 (non-insulin-dependent) diabetes. In order to test the reliability of this marker for clinical detection of Type 1 diabetes we looked for this anomaly in 150 first degree relatives of Type 1 diabetic patients, 31 relatives of Type 2 diabetic patients and 39 young non-obese diabetic patients with mild or transient hyperglycaemia. The low acute insulin response was defined by a peak insulin value (sum of plasma insulin at 2 and 5 min after glucose load, 0.3 g/kg body weight) below 50 U/ml. It was observed in 12% of the relatives of Type 1 diabetic patients (2 of them became diabetic) and in 13% of the relatives of Type 2 diabetic patients. Reproducibility of the peak insulin value in 2 subsequent tests (r=0.749) was inadequate to interpret small variations in one individual. In the population of 39 diabetic patients, 10 subsequently developed typical Type 1 diabetes, 9 were low insulin responders. In the 29 patients who are still non-insulin-dependent 3 years later, the anomaly was found in the 3 islet cell antibody-positive subjects and 11 out of 26 patients with no detectable antibodies. In conclusion, low acute insulin response to glucose is a sensitive but non-specific marker of early stages of Type 1 diabetes as this anomaly is shared by both Type 2 and Type 1 diabetes.