Beta cell response to a mixed meal in nigerian patients with type 2 diabetes

ABSTRACT: BACKGROUND: The pathophysiology of type2 diabetes involves both insulin resistance and poor beta cell function. Studies have been done in several populations to assess the relative importance of these mechanisms in individual patients. In our environment studies to assess beta cell function have been done with glucagon stimulation or an oral glucose tolerance test. This study was done to assess the response of the beta cell to a standardized mixed meal and its relationship with glycaemic control in patients with type2 diabetes. METHODS: Ninety patients with type 2 diabetes were recruited into the study. Weight, height, body mass index and waist circumference were measured. Blood samples were analysed for fasting plasma glucose (FPG) and fasting C peptide (FCP) and glycated haemoglobin (HbA1c). Patients were given their usual drugs for management of their diabetes and then served with a standard meal calculated to contain 50 g of carbohydrate, made up of 53 % carbohydrate, 17 % of protein and 30 % of lipids, providing 500 kcal. Blood samples 2 hours after the start of the meal were analysed for postprandial glucose (PPG) and postprandial C peptide (PCP). Fasting (M0) and postprandial beta cell responsiveness (M1) were calculated. RESULTS: The mean FPG and PPG were 7.51+/ 3.39 mmol/l and 11.02+/4.03 mmol/l respectively while the mean glycated haemoglobin (HbA1c) was 9.0+/2.5 %. The mean fasting C peptide was 1.44+/1.80ug/ml. Many of the patients (56.7 %) had low FCP levels. The mean postprandial C peptide was 4.0+/2.8 ng/ml. There were significant correlations between M1, HbA1c and PPG (p = 0.015, 0.024, 0.001 respectively) and also between M0, HbA1c, PPG and FPG (p = 0.001, 0.002, 0.001). HbA1c decreased across increasing tertiles of M0 (p < 0.001) and also M1 (p = 0.002). In step-wise linear regression analysis, M0 and M1 significantly predicted HbA1c. CONCLUSIONS: Many of the patients had low C peptide levels with poor beta cell response to the meal. The patients had poor glycaemic control and poor beta cell function. Both fasting and postprandial beta cell responsiveness were significant determinants of blood glucose and glycated haemoglobin levels. It is likely that putting these patients on insulin may have led to better glycaemic control in them.     

Improved meal-related insulin processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes.

The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5+/-1.5 years; BMI=29.6+/-0.5 kg/m(2); FPG=9.9+/-0.2 mmol/l; HbA1c=7.7+/-0.1 %) were studied: 29 patients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0 g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4 h post-meal) states to evaluate B-cell function. The between-treatment difference (vildagliptin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007+/-0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010+/-0.008 (p=0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240 min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p=0.023) and postprandially (p=0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.     

Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial)

Background

A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin.

Methodology/Principal Findings

The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r² = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin.

Conclusions/Significance

Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00974740","term_id":"NCT00974740"}}NCT00974740     

Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

AIMS/HYPOTHESIS: Since insulin secretion in response to exogenous gastric inhibitory polypeptide (GIP) is diminished not only in patients with type 2 diabetes, but also in their normal glucose-tolerant first-degree relatives, it was the aim to investigate the integrity of the entero-insular axis in such subjects. METHODS: Sixteen first-degree relatives of patients with type 2 diabetes (4 male, 12 female, age 50+/-12 years, BMI 26.1+/-3.8 kg/m(2)) and 10 matched healthy controls (negative family history, 6 male, 4 female, 45+/-13 years, 26.1+/-4.2 kg/m(2)) were examined with an oral glucose load (75 g) and an "isoglycaemic" intravenous glucose infusion. Blood was drawn over 240 min for plasma glucose (glucose oxidase), insulin, C-peptide, GIP and glucagon-like peptide 1 (GLP-1; specific immunoassays). RESULTS: The pattern of glucose concentrations could precisely be copied by the intravenous glucose infusion (p=0.99). Insulin secretion was stimulated significantly more by oral as compared to intravenous glucose in both groups (p<0.0001). The percent contribution of the incretin effect was similar in both groups (C-peptide: 61.9+/-5.4 vs. 64.4+/-5.8%; p=0.77; insulin: 74.2+/-3.3 vs. 75.8+/-4.9; p=0.97; in first-degree relatives and controls, respectively). The individual responses of GIP and GLP-1 secretion were significantly correlated with each other (p=0.0003). The individual secretion of both GIP and GLP-1 was identified as a strong predictor of the integrated incremental insulin secretory responses as well as of the incretin effect. CONCLUSION/INTERPRETATION: Despite a lower insulin secretory response to exogenous GIP, incretin effects are similar in first-degree relatives of patients with type 2 diabetes and control subjects. This may be the result of a B cell secretory defect that affects stimulation by oral and intravenous glucose to a similar degree. Nevertheless, endogenous secretion of GIP and GLP-1 is a major determinant of insulin secretion after oral glucose.     

Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets

Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.     

Monitoring of early and advanced glycation in relation to the occurrence of microvascular complications in children and adolescents with type 1 diabetes mellitus

The authors aimed to evaluate if the monitoring of serum advanced glycation end-products (s-AGEs) could help to predict a development of diabetic complications. Clinical and biochemical parameters including fructosamine (FAM), glycated hemoglobin (HbA1c) and serum AGEs were investigated in children and adolescents with 1 type diabetes with (+DC) and without (-DC) complications. FAM levels (in mmol/l) were significantly elevated in +DC diabetic group compared to -DC one (3.043+/-0.459 vs. 2.614+/-0.430; p<0.001) or to controls (3.043+/-0.459 vs. 1.620+/-0.340; p<0.001) as well as in -DC compared to controls (2.614+/-0.430 vs. 1.620+/-0.340; p<0.001). HbA1c (in %) were significantly elevated in +DC diabetic group compared to -DC one (10.48+/-1.83 vs. 8.41+/-1.19; p<0.001) or to controls (10.48+/-1.83 vs. 5.0+/-0.38, p<0.001) and also in -DC compared to controls (8.41+/-1.19 vs. 5.0+/-0.38; p<0.001). Serum AGEs levels (in A. U.) were significantly higher in +DC group than in -DC (73.0+/-14.09 vs. 65.8+/-9.05; p<0.05) and in group +DC than in controls (73.0+/-14.09 vs. 60.17+/-13.78; p<0.05), whereas there was no difference between -DC and controls. FAM correlated with HbA1c in both diabetic groups (+DC: r=0.374; p<0.05; -DC: r=0.719; p<0.001), but not in controls. Serum AGEs were correlated with HbA1c (r=0.478; p=0.003) in +DC, but not in -DC or controls. Enhanced serum AGEs levels show that they could be not only an attendant phenomenon of microangiopathies, but also a predictor of their development.     

Vildagliptin in drug-na?ve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study.

This 24-week double-blind, randomized, multicenter, placebo-controlled, parallel-group study was performed in 632 drug-na?ve patients with type 2 diabetes to assess efficacy and tolerability of vildagliptin (50 mg qd, 50 mg bid, or 100 mg qd). HbA1c decreased modestly in patients receiving placebo (Delta=-0.3+/-0.1%) and to a significantly greater extent in patients receiving vildagliptin 50 mg qd (Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/-0.1%, p<0.01 for all groups VS. placebo) from an average baseline of 8.4%. In patients diagnosed >or=3 months before enrollment, HbA1c increased with placebo (Delta=+0.2+/-0.2%) and between-treatment differences (vildagliptin-placebo) were -0.8+/-0.2% (p<0.001), -0.7+/-0.2% (p=0.003), and -0.9+/-0.2% (p<0.001) with vildagliptin 50 mg qd, 50 mg bid, and 100 mg qd, respectively. There was no apparent dose-response in the overall population; however, in patients with high baseline HbA1c, there were greater reductions with either 100 mg dose regimen (Delta=-1.3+/-0.2% and -1.4+/-0.2%) compared to 50 mg qd (Delta=-0.8+/-0.1%). Body weight decreased modestly in all groups (by 0.3 to 1.8 kg). The incidence of adverse events was similar across all groups and 相似文献   

Reversibility of autonomic nerve function in relation to rapid improvement of glycemic control.

To determine the reversibility of autonomic nerve function in relation to the rapid improvement of glycemic control, we studied 54 patients with type 2 diabetes mellitus (33 men and 21 women; mean age, 49+/-8 years; mean duration of diabetes, 10+/-7 years). For 4 weeks of admission, the subjects were placed on strict dietary therapy, and 10 of them were under dietary therapy, 16 initially continued treatment with oral hypoglycemic agents, while 28 were treated with insulin. We measured the dark-adapted pupillary area (DAPA) by infrared photography, an indicator of diabetic autonomic neuropathy, on the second and 28th day after hospitalization. The change in FPG (delta FPG = - 111+/-49 mg/dl; mean +/- SD, p<0.001) and the change in HbA1c (delta HbA1c = -1.3+/-0.3%, p<0.001) were significantly improved. We observed significant improvements in the change in DAPA (delta DAPA) of all patients (25.1+/-11.0 vs. 25.7+/-11.6 mm2, delta DAPA = 0.6+/-1.4 mm2, p<0.01) and in those of patients without retinopathy (delta DAPA = 1.0+/-0.6 mm2, p<0.01). No change was observed in those of patients with retinopathy (delta DAPA= -0.02+/-0.3 mm2, NS). The delta DAPA was related to the delta HbA1c (r = -0.479, p<0.001) and also to the diabetic duration (years, r = -0.517, p<0.001). These findings suggest that a rapid improvement of glycemic control improves autonomic nerve function observed in type 2 diabetes with shorter duration. Particular attention should be paid to maintaining strict glycemic control at the stage of diabetic patients without retinopathy and those with shorter duration.     

Reduction in urine C-peptide clearance rate after metabolic control in NIDDM patients

One hour urine C-peptide and creatinine clearance rates were determined simultaneously in 25 hospitalized patients with non-insulin-dependent diabetes mellitus (NIDDM) undergoing sulfonylurea and/or diet treatment. The studies had been performed after an overnight fast on the second day of admission and on a day soon before discharge, with intervals of 18.9 +/- 7.0 days. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) values decreased significantly at the second examination as compared to the initial values (FPG: 101 +/- 20 mg/dl vs. 161 +/- 47 mg/dl, p less than 0.005; HbA1c: 7.3 +/- 1.5% vs. 8.4 +/- 1.7%, p less than 0.005). The urine C-peptide clearance rate also decreased significantly after metabolic control (0.75 +/- 0.36 l/hr vs. 1.06 +/- 0.54 l/hr, p less than 0.005). Meanwhile, the urine creatinine clearance rate tended to decrease, but the difference was not significant (3.69 +/- 2.04 l/hr vs. 4.87 +/- 2.98 l/hr) at the second examination. The data suggest that the urine C-peptide clearance rate is susceptible to the effects of the fluctuation of metabolic states in NIDDM patients. In order to use urinary C-peptide for a follow up study of pancreatic B-cell secretion, the changes in C-peptide clearance under various metabolic conditions must be taken into account.     

Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes.

Inhibition of dipeptidyl peptidase-4 enhances the activity of incretin hormones, improving glycemic control in subjects with type 2 diabetes. This twelve-week randomized, double-masked, placebo-controlled study assessed the efficacy and tolerability of the specific and potent oral dipeptidyl peptidase-4 inhibitor, vildagliptin (25 mg, bid, n=70) VS. placebo (bid, n=28) in previously diet-treated subjects with type 2 diabetes. Standardized meal tests were performed at baseline and endpoint. The between-group difference in adjusted mean change in HbA1c from baseline to endpoint was - 0.6 +/- 0.2 % (p=0.0012) for the whole cohort (baseline 8.0 %) and -1.2 % for subjects with baseline HbA1c 8.0 - 9.5 %. Fasting glucose and mean prandial glucose were reduced by 1.1 +/- 0.4 (p=0.0043) and 1.9 +/- 0.5 mmol/l (p <0.0001), respectively. The between-group differences in corrected insulin response at peak glucose and mean prandial C-peptide were + 0.06 +/- 0.02 (p=0.0258) and + 0.10 +/- 0.03 nmol/l (p=0.0031), respectively. Vildagliptin had no effect on fasting lipid levels or body weight. The incidence of adverse events was similar in subjects receiving placebo (71.4 %) and vildagliptin (55.7 %). CONCLUSION: monotherapy with vildagliptin is well tolerated and improves glycemic control in diet-treated subjects with type 2 diabetes. Concomitant improvements in beta-cell function were also observed. Subjects with higher baseline HbA1c levels showed greater response.     

CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3

Background

Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca²⁺ channel Ca_V2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes.

Methodology/Principal Findings

In 595 GAD-negative, drug naïve patients (mean±SD; age: 58.5±10.2 yrs; BMI: 29.9±5 kg/m², HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05−0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05).

Conclusions/Significance

In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.     

Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial

Background

Recent evidence suggests that the lipid-lowering agent atorvastatin is also a potent immunomodulator. The aim of this study was to investigate the possible effect of atorvastatin on the decline of residual beta cell function in recent-onset type 1 diabetes.

Methods and Findings

The randomised placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and islet autoantibodies (mean age 30 years, 40% females), in 12 centres in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. An intent-to-treat analysis was performed. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, median fasting serum C-peptide levels dropped from baseline to 12 and 18 months in the placebo group (from 0. 34 to 0.23 and 0.20 nmol/l, p<0.001) versus a nonsignificant decline in the atorvastatin group (from 0.34 to 0.27 and 0.30 nmol/l, ns). Median stimulated C-peptide concentrations declined between baseline and 12 months (placebo from 0.89 to 0.71 nmol/l, atorvastatin from 0.88 to 0.73 nmol/l, p<0.01 each) followed by a major loss by month 18 in the placebo group (to 0.48 nmol/l, p = 0.047) but not in the atorvastatin group (to 0.71 nmol/l, ns). Median levels of total cholesterol and C-reactive protein decreased in the atorvastatin group only (p<0.001 and p = 0.04). Metabolic control was similar between groups.

Conclusions

Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00974740","term_id":"NCT00974740"}}NCT00974740     

A Five-Year Prospective Study of Diabetic Retinopathy Progression in Chinese Type 2 Diabetes Patients with “Well-Controlled” Blood Glucose

Purpose

To determine the progression rate and risk factors for diabetic retinopathy (DR) in Chinese type 2 diabetic patients who have reached the target hemoglobin A1c (HbA1c) level recommended by the American Diabetes Association.

Methods

This was a 5-year community-based prospective study. The study population consisted of patients with type 2 diabetes with HbA1c less than 7.0%. Demographic information, systemic examination results and ophthalmological test results for each participant were collected. The outcome of this study was the progression of DR, which was defined as an increase in DR grade in one or both eyes at the final visit in comparison to the baseline status. The association between each potential risk factor and DR progression was studied.

Results

A total of 453 patients with HbA1c less than 7.0% were included in the study group. In 146 patients (32.22%), DR developed or progressed during the five-year follow-up. Baseline HbA1c level was the only independent risk factor for DR progression (p<0.01, OR = 2.84, 95%CI: 2.11~3.82). The logistic regression function suggested that the possibility of DR progression increased fastest when baseline HbA1c increased from 5.2% to 6.4%. The 5-year DR progression rate in patients with baseline HbA1c less than 5.2%, between 5.2% and 6.4%, and over 6.4% were 19.62%, 24.41%, and 76.83%, respectively.

Conclusions

To slow the progression of DR in Chinese patients with type 2 diabetes, more intensive glucose control is recommended.     

Insulin requirement profiles and related factors of insulin pump therapy in patients with type 2 diabetes

Continuous subcutaneous insulin infusion(CSII) is an effective therapy to control hyperglycemia in both patients with type 1 diabetes and type 2 diabetes.However,there is little data investigating the insulin dose setting during CSII therapy in type 2 diabetes to achieve optimal glycemic control and avoid the risk of hypoglycemia.Thus,this study is aimed to assess the dose characteristics of insulin requirement and explore the related clinical factors in patients with type 2 diabetes who were treated with CSII.A total of 327 patients(195 males) aged 52.9±12.5 years old were included in this study.Patients were treated with CSII to achieve the target fasting capillary blood glucose(4.4-7.0 mmol L ~(-1)) and 2-h postprandial capillary blood glucose(4.4-10.0 mmol L ~(-1)) by adjusting insulin infusion according to the seven-point capillary blood glucose profiles.Total daily insulin dose(TDD),total daily insulin dose per kilogram(TDD kg-1) and the ratio of total basal insulin dose(TBD) to TDD(%TBa) were calculated after patients achieved the glucose targets for at least 3 days via 1-2 weeks of CSII treatment.And insulin dose,insulin dosing patterns and the relevant clinical factors were analyzed.The mean ratio of basal/bolus insulin distribution of all patients was 40%:60%.Patients with central obesity needed more TDD(51.3±17.1 U versus 43.5±14.0 U,P0.05) and TDD kg ~(-1)(0.8±0.3 U kg ~(-1) versus 0.7±0.2 U kg ~(-1),P0.05) than those without central obesity.Pearson's correlation analysis demonstrated that TDD was positively correlated with body mass index(BMI),waist circumference(WC),baseline fasting plasma glucose(FPG),fasting C-peptide level,2 h-postprandial C-peptide level and time to achieve glycemic target(all P0.05);TDD kg ~(-1) was positively correlated with waist-to-hip ratio(WHR),baseline FPG,glycosylated hemoglobin Ale(HbAlc),fasting C-peptide level and time to achieve glycemic target,and negatively correlated with BMI(all P0.05).Multiple linear regression analyses revealed that BMI(β=1.796,P0.01),WC(β=0.109,P0.01),baseline FPG(β=1.459,P0.01) and HbAlc(β=0.930,P=0.021) were independently related to TDD.Gender(β=-0.107,P=0.003),WC(β=0.005,P=0.029),baseline FPG(β=0.025,P0.01) and HbAlc(β=0.016,β=0.007) were independently associated with TDD kg ~(-1).Gender(β=-0.015,P=0.048) and disease duration(β=0.134,P=0.029) were independently associated with %TBa.%TBa is around 40% in Chinese patients with type 2 diabetes treated with CSII when glycemic control is achieved.In addition to body weight or BMI,WC and glucose levels before CSII should be considered to set TDD.Patients with central obesity or poor glycemic control might need more TDD.Higher %TBa should be considered in female patients or patients with longer disease duration.     

Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control.

New scores and biochemical markers have recently been published for diagnosis of insulin resistance and beta-cell dysfunction (such as intact proinsulin, adiponectin, IRISII-score). One goal of this 6-month prospective controlled study was to evaluate the impact of pioglitazone (45 mg) vs. glimepiride (1-6 mg, in the intend to optimize therapy) on these markers. Observation parameters were: IRIS-II score, HOMA-score, ATP III score, HbA (1c), fasting glucose, lipids, intact proinsulin, adiponectin, and adverse events. The study was completed by 173 patients (66 female, 107 male, age +/- STD: 63 +/- 8 years, disease duration: 7.2 +/- 7.2 years, HbA (1c): 7.53 +/- 0.85 %, pioglitazone arm: 89 patients). The groups were not different for any of the observation parameters at baseline, and a similar reduction in HbA (1c) was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for the IRIS-II and HOMA scores (p < 0.001 vs. glimepiride at endpoint) fasting glucose (p < 0.001), insulin (p < 0.001), LDL/HDL ratio (p < 0.001), hsCRP (p < 0.05), intact proinsulin (p < 0.001), and an increase was seen in HDL (p < 0.001), adiponectin (p < 0.001) and BMI (p < 0.001). In conclusion, treatment with pioglitazone resulted in an improvement of markers for insulin resistance and beta-cell dysfunction, independent from blood glucose control. Adiponectin, intact proinsulin, and the IRIS-II score may be suitable parameters for monitoring of these additional beneficial therapeutic effects.     

Angiotensin converting enzyme (ACE) activity levels in insulin-independent diabetes mellitus and effect of ACE levels on diabetic patients with nephropathy

Involvement of complications is considered to be one of the major factors in the prognosis of diabetes mellitus (DM). Recent studies indicate that most diabetic complications such as nephropathy and hypertension are vascular-originated. Renin-angiotensin involvement, especially changes in ACE activity level, is considered to be a key factor since ACE converts angiotensin I to angiotensin II which is a potent vasoconstrictor and plays a vital role in the regulation of blood pressure. Our present study focused on ACE activity levels along with blood glucose and HbA(1c) levels in diabetic patients with (n=18) or without (n=25) nephropathy as compared to control subjects (n=25). Blood glucose levels were significantly higher in both diabetic groups compared to controls (p<0.001). On the other hand, compared to controls, blood HbA(1c) levels were slightly higher in DM patients without complications whereas they were significantly increased in nephropatic DM patients (p<0.001). There was a very strong increase (p<0.001) at the level of ACE activity in both of the diabetic groups (with nephropathy: 47.11+/-3.70 U l(-1); without complications: 43.72+/-2.93 U l(-1); controls: 25.15+/-2.30 U l(-1)). ACE activity levels were also significantly higher in diabetic patients with nephropathy than in type II DM patients without complication (p<0.01). Our results demonstrate that ACE activity levels are increased in diabetic patients. Additional significant increase in ACE activity levels in diabetic patients with complications such as nephropathy supports the hypothesis that ACE activity has an essential role in the development of complications in diabetes.     

Sustained normoglycemia and remission phase in newly diagnosed type I diabetic subjects. Comparison between continuous subcutaneous insulin infusion and conventional therapy during a one year follow-up

After onset of type I diabetes 7 diabetics were randomized to subcutaneous insulin pump treatment (CSII) (age 12 to 29 years, mean: 21 years) and 7 diabetics to conventional insulin treatment (CI) (age 14 to 28 years, mean: 21 years). HbA1, glycosylated serum proteins and mean blood glucose (MBG) as parameters of metabolic control were determined monthly. After 2 months both groups showed HbA1 values in the normal range. Mean MBG values were (mean +/- SD) 116 +/- 7 mg/dl for CSII and 118 +/- 14 mg/dl for CI. Residual insulin secretion was determined monthly by fasting C-peptide. After 14 days, 5, 7, 8 months fasting C-peptide values were significantly (P less than 0.05) higher in CI. After one year fasting C-peptide was comparable in both groups (CSII and CI mean: 0.06 nmol/l). The administered insulin dose was comparable in both groups with a 55% reduction of insulin dose after 5 months in CSII (0.35 +/- 0.15 U/kg/24 h) and in CI after 7 months (0.31 +/- 0.28 U/kg/24 h). After 12 months of insulin therapy about 60% of the initial insulin dose was injected in both groups. 1 patient on CSII (12 years) and 2 patients on CI (15, 28 years) showed a complete remission (for 3-9 months) with no exogenous insulin and normal HbA1 values. 50% of the patients had episodes where they did need less than 0.2 U/kg/24 h insulin to maintain optimal diabetic control (3 CSII, 4 CI). During the first year of insulin treatment in type I diabetes with CSII as well as with CI a comparable near normalisation of diabetic control could be achieved.     

Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion.

Interactions between leptin and insulin have been shown previously, in vitro and in vivo. In this study, we evaluate the associations of leptin levels with insulin secretion and insulin sensitivity in type 2 diabetes. Fasting leptin levels, HbA 1c, glucose, insulin, C-peptide, intact and des-31,32-proinsulin were measured in 100 non-insulin-treated type 2 diabetic patients. Glucose, insulin and C-peptide were measured 2 hours after an oral glucose load. Insulin resistance and beta-cell function were calculated using HOMA. Leptin levels were found to be associated with all measures of beta-cell secretion: with fasting and 2 hours insulin and C-peptide, with intact and des-31,32-proinsulin concentrations, and with beta-cell secretion estimated with HOMA. This association was independent of age and body fat in women, but in men, associations with insulin and C-peptide weakened after controlling for fat mass, whereas those with intact and des-31,32-proinsulin disappeared. Fasting insulin and C-peptide levels were also significant in multiple regression analyses, besides gender and fat mass. Insulin resistance, as assessed by HOMA, was strongly correlated with leptin, also after correction for age and fat mass in both genders. We conclude that, besides fat mass and gender - the main determinants for leptin levels in type 2 diabetic subjects as in healthy subjects - insulin secretion and the degree of insulin resistance also seem to contribute significantly to leptin levels.     

Biomarker potential of C-peptide for screening of insulin resistance in diabetic and non-diabetic individuals

Insulin resistance is a hallmark feature of type-2 diabetes mellitus (T2DM). We determined the homeostatic model assessment insulin resistance (HOMA-IR) and evaluated its association with C-peptide, insulin, fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) in T2DM patients and non-diabetic subjects. This study comprised a total of 47 T2DM patients and 38 non-diabetic controls. Venous blood samples from all the subjects were collected and sera were analyzed for FBG, HbA1c, insulin and C-peptide using an autoanalyzer. HOMA-IR was calculated using the following equation: HOMA-IR?=?fasting insulin (µU/ml)?×?fasting glucose (mmol/L)/22.5. There was a significant increase in the levels of FBG and HbA1c in diabetic patients. Although the levels of C-peptide and insulin did not differ significantly between the two groups, a significant increase in HOMA-IR was observed in T2DM patients. Both insulin and C-peptide were significantly correlated with HOMA-IR. In conclusion, C-peptide may serve as a simple and convenient predictor of HOMA-IR.     

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA₁c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA_IR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA_IR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.