Obesity does not modulate insulin secretion in Indian patients with non-insulin-dependent diabetes in the young

The insulin response to a 100-g oral glucose load was studied in 40 obese (percent desirable weight greater than or equal to 120%) and 40 nonobese (less than 120%) age- and sex-matched Indian patients with non-insulin-dependent diabetes in the young. There were no significant differences between the obese and nonobese patients with respect to their insulin and glucose responses. Thus, it appears that obesity does not exert a significant modulating effect on insulin secretion in patients with fasting hyperglycemia.     

Essential hypertension and insulin resistance in non-insulin-dependent diabetes

A recent study has shown that young, lean, hypertensive subjects are more insulin resistant than corresponding normotensive subjects. Whether this finding can also be demonstrated in the presence of non-insulin-dependent diabetes mellitus (NIDDM) is not known. Therefore, the degree of insulin resistance was studied in 26 middle-aged hypertensive patients with NIDDM (11 men, 15 women) and 14 normotensive patients with NIDDM (eight men, six women) matched for age, metabolic control and the duration of diabetes, utilizing the glucose clamp technique. Non-obese NIDD patients (body mass index less than 27.0 kg m-2) with hypertension (n = 11) had significantly lower glucose disposal rates (GDRs) during the last 60 min of euglycaemic (5.5 mmol l-1) and hyperinsulinaemic (approximately 600 pmol l-1) clamp studies than NIDD patients without hypertension (n = 6) (782 +/- 94 vs. 1418 +/- 97 mumol m-2 min-1, P less than 0.05). In contrast, GDRs were similar in obese NIDD patients with (n = 15) and without (n = 8) hypertension (802 +/- 90 vs. 849 +/- 90 mumol m-2/min-1, respectively, P = NS). Basal hepatic glucose output, suppression of hepatic glucose production during hyperinsulinaemia and insulin secretion capacity did not differ between hypertensive and normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

A variant insulin promoter in non-insulin-dependent diabetes mellitus.

To test the hypothesis that alterations in regulatory regions of the insulin gene occur in a subset of patients with non-insulin-dependent diabetes mellitus (NIDDM), the promoter region was studied by polymerase chain reaction (PCR) amplification directly from genomic DNA, followed by high-resolution polyacrylamide gel electrophoresis under nondenaturing conditions. By using this method a previously identified HincII polymorphism (GTTGAC to GTTGAG at position-56) in American Blacks was readily detected, indicating that single base changes could be observed. In the course of screening the insulin promoter from 40 American Black subjects with NIDDM, an apparent larger allele was found in two individuals. Both patients were shown to have in addition to a normal allele, a larger allele containing an 8-bp repeat, TGGTCTAA from positions -322 to -315 of the insulin promoter. To facilitate rapid screening for the 8-bp repeat, a high-resolution agarose gel electrophoretic analysis was adopted. DNA from American Black NIDDM subjects (n = 100) and nondiabetic subjects (n = 100) was PCR amplified and analyzed. The 8-bp repeat was present in five NIDDM subjects, and one nondiabetic subject. DNA from Mauritius Creoles, also of African ancestry, was analyzed, and the 8-bp repeat was present in 3 of 41 NIDDM subjects, and 0 of 41 nondiabetic subjects. Analysis of glucose metabolism in three presumed normal sibs of an NIDDM patient with an 8-bp repeat revealed that one sib had overt diabetes, and two sibs were glucose intolerant, but there was no consistent segregation of the insulin promoter variant with the diabetes phenotype. The variant promoter was not present in 35 Caucasian NIDDM patients or in 40 Pima Indians. To test the biological consequences of the 8-bp repeat sequence in the insulin promoter, a normal and variant promoter were subcloned into a luciferase plasmid, and reporter gene activity assessed by transient transfection into mouse insulinoma (beta TC1) and hamster insulinoma (HIT) cells. The promoter activity of the variant allele was found to be reduced to 37.9 +/- 10.3% of the activity of the normal promoter in HIT cells (P less than 0.01, n = 4), and 49.1 +/- 6.4% in beta TC1 cells (P less than 0.01, n = 6). These data thus suggest that a naturally occurring variant of the insulin promoter may contribute to the diabetes phenotype in 5-6% of Black NIDDM patients.     

Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands.

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.     

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.     

Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin-dependent diabetes mellitus

Bradykinin infusion has been shown to improve glucose metabolism in non-insulin-dependent diabetic subjects (NIDD). Therefore, we tested the following hypothesis: inhibition of Kininase II, the bradykinin (BK) degrading enzyme, by captopril may also improve glucose metabolism in NIDD. Immediate effects of captopril on total body and peripheral glucose disposal were examined in five normotensive, normal weight NIDD and compared with five NIDD control subjects, well matched for age, weight and degree of fasting hyperglycaemia. The euglycaemic insulin clamp technique was employed in combination with the forearm catheter technique. After 90 min of insulin infusion a single dose of 25 mg captopril was administered orally, whereas in the control group a placebo was given. Captopril lead to a significant rise in total body glucose disposal and forearm glucose uptake, while in the control group no change was observed. Simultaneously, captopril lead to reduction in muscular release of lactate and pyruvate. We conclude that these results demonstrate the stimulatory effect of captopril on insulin-induced glucose disposal of the whole body, which appears to be a result of increased glucose utilization by peripheral tissues. Because of the described insulin-like activity of bradykinin, the concomitant accumulation of local kinins by captopril-induced inhibition of kininase II may represent an attractive hypothesis to explain the generated data sufficiently.     

Impaired insulin secretion in the spontaneous diabetes rats

Dynamics of insulin and glucagon secretion were investigated by using a new model of spontaneous diabetes rats produced by the repetition of selective breeding in our laboratories. The perfusion experiments of the pancreas showed that the early phase of insulin secretion to continuous stimulation with glucose was specifically impaired, although the response of the early phase to arginine was preserved. The glucose-induced insulin secretion in the nineth generation (F8) which had a more remarkably impaired glucose tolerance was more reduced than in the sixth generation (F5). No significant difference of glucagon secretion in response to arginine or norepinephrine was noted between the diabetes rats and control ones. The present data indicate that the defective insulin secretion is a primary derangement in a diabetic state of the spontaneous diabetes rat. This defect in the early phase of glucose-induced insulin secretion suggests the specific impairment of the recognition of glucose by the pancreatic beta-cells. The spontaneous diabetes rats are very useful as a model of disease for investigating pathophysiology of non-insulin dependent diabetes mellitus.     

氯氮平对体外培养大鼠胰岛分泌功能的影响剂量基础胰岛素分泌无关

背景氯氮平所致的糖代谢障碍越来越引起内分泌科医生的关注,胰岛素抵抗被认为与其发生有关,那么氯氮平是否也直接影响胰岛分泌功能.目的观察不同浓度氯氮平在不同条件下对体外培养大鼠胰岛分泌功能的影响.设计完全随机分组设计,对照实验,采用一元方差分析比较实验组和对照组之间的差异,采用LSD-t检验作多个样本间的两两比较(多重比较).单位武汉大学人民医院精神卫生中心.材料实验于2003-09/2004-01在武汉大学口腔医院实验中心完成.选用清洁级健康雄性Wistar大鼠3只.方法[1]采用经典的胶原酶消化法分离、纯化胰岛.[2]以含2g/L牛血清白蛋白和3.3 mmol/L葡萄糖的Hanks液每孔1 mL,预孵育30 min,弃上清.每12孔为一组,共5组对照组的孵育液含1 g/L二甲基亚砜、3.3 mmol/L或16.7 mmol/L的葡萄糖液1 mL;4个不同浓度氯氮平组的孵育液除含有上述成分外,还分别含浓度为0.2,1.0,5.0或10.0μmoL/L氯氮平;各组有6孔继续孵育1 h,另外6孔继续孵育4 h;吸取上清液,保存于-20℃冰箱中待测.重复3次.采用放射免疫分析法测定上清液中胰岛素分泌量.[3]采用一元方差分析(ANOVA)比较实验组和对照组之间的差异,采用LSD-t检验作多个样本间的两两比较(多重比较).主要观察指标培养液葡萄糖浓度为3.3,16.7 mmol/L,作用1,4 h各组胰岛素分泌量比较.结果[1]培养液葡萄糖浓度为3.3 mmol/L,培养1 h,氯氮平各浓度组胰岛素分泌量与对照组相近(P＞0.05);培养4 h,4种浓度氯氮平组胰岛素分泌量明显低于对照组[(0.92±0.4),(1.02±0.3),(1.06±0.4),(0.74±0.2),(1.66±0.4)mU/IEQ,P＜0.05],但各浓度组间差异不明显(P＞0.05).[2]培养液葡萄糖浓度为16.7 mmol/L,培养1和4 h,4种浓度氯氮平组胰岛素分泌量均与对照组相近(P＞0.05).结论氯氮平抑制基础胰岛素分泌,与剂量无关.     

Polymorphisms in the 5'-flanking region of the insulin gene and non-insulin-dependent diabetes

DNA insertions in the 5'-flanking region of the insulin gene have been studied by Southern-blot-hybridization techniques using a cloned gene probe in 159 unrelated Caucasians. Subjects homozygous for a large DNA insertion at this locus were found to have a higher risk of concurrence of non-insulin-dependent diabetes (NIDD) than controls (P less than 0.01). Analysis of a single large NIDD pedigree (n = 67 in four generations; 11 diabetic subjects) showed no linkage between the size of DNA inserts and diabetes (Lod score = -5.7), suggesting a separate diabetogenic locus (or loci) in this family.     

Effect of insulin treatment on serum lipoprotein(a) in non-insulin-dependent diabetes

Abstract. In order to evaluate whether Lp(a), a lipoprotein that is potentially thrombogenic and atherogenic, is a potential risk factor for CAD in non-insulin-dependent diabetes (NIDDM), we compared the Lp(a) and its distribution in 145 NIDDM patients with that in 94 healthy control subjects. Furthermore, we studied the effect of insulin treatment on serum Lp(a) in 108 patients with NIDDM. Male and female NIDDM patients had similar Lp(a) concentrations to healthy controls (median value 167 mg L^-1, range 15–1550 mg L^-1 vs. 157 mg L^-1, range 15–919 mg L^-1, NS and 92, range 15–1190 mg L^-1 vs. 103 mg L^-1, range 15–842 mg L^-1, NS). Also, the cumulative distribution of Lp(a) did not differ between the NIDDM patients and healthy subjects. Insulin treatment increased Lp(a) in diabetics with a Lp(a) concentration of less than 300 mg ^-1L, but this effect was not related to the concomitant improvement in metabolic control (mean change (±SEM) of HbA_1c from 9.80±0.15 to 8.00±0.12; P < 0.001). In subjects with elevated Lp(a) concentrations (>300 mg L^-1) the Lp(a) concentration was unaffected by insulin, despite a similar improvement in glycaemic control. These results suggest that insulin may modulate the concentration of Lp(a).     

Insulin antibodies in non-insulin-dependent diabetes mellitus: effect of treatment with semisynthetic human insulin

This multicenter study of patients with non-insulin-dependent diabetes mellitus (NIDDM) was undertaken (1) to determine the incidence of insulin antibody formation in such patients before exposure to exogenous insulin; (2) to assess the long-term immunologic response to semisynthetic human insulin (ssHI) in new insulin users and in patients transferred from animal insulin; and (3) to document the efficacy and safety of ssHI in both new and transfer patients. In addition, a substudy at one participating center was designed to compare the effects of a twice-daily versus a once-daily regimen in initiating ssHI therapy in new patients with uncontrolled NIDDM. Among the 37 new patients, only one had detectable insulin antibody levels before administration of insulin. After ssHI therapy was begun, this patient's antibody levels rapidly fell below the assay's limit of detection. Detectable levels of antibodies to human insulin were found in only 36% of 28 new patients after 12 months of therapy. As expected, the prevalence of insulin antibodies among animal-insulin users was high: 82% of the 17 transfer patients had detectable insulin antibody levels (mean, 2.27 mU/ml) at baseline. After six months of treatment with ssHI, antibody levels decreased significantly (mean, 0.75 mU/ml; P less than 0.05). Control of glycemia was assessed by measurement of glycosylated hemoglobin. Values decreased significantly (P less than 0.01) in the new patients after the introduction of ssHI and remained stable in the transfer group after initiation of ssHI therapy. Hypoglycemic episodes were infrequent in both groups. In initiating ssHI therapy in new patients hospitalized with uncontrolled NIDDM, a twice-daily regimen resulted in a more rapid normalization of glycemia and earlier discharge than did the standard once-daily regimen. In conclusion, the results of this study provide further evidence that NIDDM and insulin-dependent diabetes mellitus (IDDM) are immunologically different disorders, with the immune system probably not involved in the pathogenesis of NIDDM. The data also indicate that ssHI is less immunogenic than animal insulin and that it is effective and safe in the management of NIDDM both in first-time insulin users and in patients transferred from animal-species insulin. Thus ssHI would appear to be useful in treating NIDDM, especially in patients who require intermittent insulin therapy.     

The effect of bran on glucose kinetics and plasma insulin in non-insulin-dependent diabetes mellitus

Experiments were carried out on two groups of diabetic patients treated (1) by diet alone (group A) and (2) by diet and oral agents (group B), the latter being discontinued 3 days before each test. All patients were tested twice. To measure rates of glucose metabolism, 3H-3-glucose was infused before and during a standard 3-h 50-g oral glucose tolerance test. 14C-1-glucose was added to the glucose solution and the percentage of ingested glucose that appeared in peripheral blood was calculated. Bran improved glucose tolerance only in group B patients by delaying the peripheral appearance of ingested glucose but had no effect on glucose absorption in group A. In contrast, patients in group A showed a marked reduction in their insulin response when bran was mixed with the glucose. Despite this reduction, glucose tolerance, the metabolic clearance rate (MCR) of glucose, and all other rates measured were unaffected by bran. Thus we conclude that in patients adequately controlled by diet alone, the effect of insulin was potentiated when bran was ingested, but the mechanism involved remains obscure.     

Non-insulin dependent diabetes mellitus: defects in insulin secretion

Abstract. NIDDM is a heterogeneous disorder, characterized by defects in insulin secretion as well as in insulin action. Several pathophysiological mechanisms are involved in the development of disturbances in insulin secretion. One of the histological features of islets of NIDDM patients is the deposition of amyloid-like material. Accumulation of amyloid over many years can lead to slowly progressive disruption of islet architecture and possibly to some of the abnormalities in insulin secretion, as found in NIDDM patients. Loss of pulsatility is the earliest detectable abnormality of insulin secretion in the disease, either as a specific early defect or as a disturbance caused by minimally elevated blood glucose levels. Although it has been shown that maximum insulin release is decreased by 50% in NIDDM, the B-cell sensitivity to glucose appears to be normal. Coregulatory factors such as prostaglandins do not play a major role in the derangements of insulin secretion in NIDDM. An imbalance between stimulatory and inhibitory endorphins, or in sympathetic tone may be of more importance. Hyperglycaemia by itself has a deleterious effect on insulin release, and may perpetuate the disturbances of insulin secretion.     

Insulin and C-peptide secretion in non-insulin-dependent diabetes mellitus and its response to dietary therapy

We studied insulin and C-peptide levels in patients with non-insulin-dependentdiabetes mellitus (NIDDM) during standard oral or intravenousglucose tolerance tests (GTT) at the time of diagnosis and after3 months dietary therapy. On the second occasion they also hadan ‘augmented’ GTT, in which slow intravenous infusionof glucose raised basal plasma glucose to a level similar tothat at the time of diagnosis. Eight patients had oral tests,and seven patients intravenous tests. In both groups, dietarytherapy significantly reduced fasting and peak plasma glucose(p<0.05 for oral; p<0.01 for intravenous GTT). Serum insulinlevels during conventional oral GTT were not significantly differentafter dietary therapy compared to diagnosis, but were significantlyhigher during the ‘augmented’ oral GTT (p<0.05).In those patients who underwent intravenous GTT, there was asignificant increase in both the total amount of insulin secreted(0–60 min) and in first-phase insulin secretion (0–10min) during the ‘augmented’ test compared to diagnosis(p<0.01), but first-phase insulin secretion during the conventionalintravenous GTT was unchanged. Serum C-peptide responses werealso greater during ‘augmented’ tests (p<0.05),similar in pattern to serum insulin. There is a relative deficiencyin insulin secretion in untreated NIDDM, which can be reversedby dietary therapy. It is essential to study insulin and C-peptidesecretion in controlled ‘fasting’ glucose conditions.     

Feedback inhibition of insulin secretion in type 2 diabetes.

1. The purpose of the present study was to examine the ability of insulin to inhibit its own secretion in type 2 diabetes independently of the prevailing plasma glucose concentration. 2. The responses of the plasma C-peptide concentration to sustained hyperinsulinaemia were assessed during a 200 min isoglycaemic clamp study in 14 patients with type 2 diabetes and seven age- and weight-matched control subjects. The arterialized venous plasma glucose concentration was clamped at approximately 0.3 mmol/l below each subject's own basal level and was not permitted to rise above the basal level. 3. In the fasting state, the plasma C-peptide concentration was slightly, but not significantly, higher in the diabetic patients than in the control subjects (667 versus 413 pmol/l, respectively, P = 0.07), but it remained significantly higher in the diabetic patients during the clamp studies in absolute terms (minimum plasma C-peptide concentration 400 pmol/l in diabetic patients versus 151 pmol/l in control subjects, P less than 0.05) and was suppressed to a lesser extent when expressed as a percentage change from basal (35.8% in diabetic patients versus 59.4% in control subjects, P less than 0.01). 4. In order to investigate whether a high plasma glucose concentration was maintaining the plasma C-peptide concentration in the diabetic patients, six of these patients underwent a second clamp study at euglycaemia (plasma glucose concentration 5.2 mmol/l). Under these conditions, the plasma C-peptide concentration was suppressed to the same extent as in the control subjects (from 623 to 195 pmol/l, a change of 62.7%).(ABSTRACT TRUNCATED AT 250 WORDS)     

New strategies for basal insulin treatment in type 2 diabetes mellitus

BACKGROUND: The clinical progression of type 2 diabetes mellitus (DM) is well understood. Glycemic control gradually deteriorates, and progression of DM eventually leads to an increased risk for microvascular and macrovascular complications. Reassessment of current insulin treatment strategies leading to restoration of glycemic control is essential to prevent or stop the progression of type 2 DM and its complications. OBJECTIVE: The purpose of this article was to review the importance of instituting a strategy of basal insulin therapy in patients with type 2 DM. METHODS: Relevant articles were obtained through an online search of PubMed and MEDLINE for literature published from 1990 to 2003. The search terms used were insulin therapy, combination oral therapy, treatment failure, glycemic control, insulin analogues, insulin glargine, basal insulin, and microvascular complications. RESULTS: Large-scale intervention trials, such as the United Kingdom Prospective Diabetes Study (UKPDS), have reported that patients with type 2 DM treated with oral combination therapy are unable to maintain glycemic control. These observations have led to a reassessment of the role of insulin therapy in type 2 DM. The importance of tight glycemic control through the aggressive use of insulin early in the course of the disease is apparent from the UKPDS, Diabetes Control and Complications Trial, and other, smaller studies. Considerable evidence indicates that initiating a basal insulin-replacement strategy with an existing oral regimen can result in regaining glycemic control. Evidence emerging from recent studies indicates that use of intensive insulin therapy early in the course of the disease may have a positive clinical impact on outcome and slow the progression of complications. The availability of basal insulin analogues has expanded treatment options and improved the efficacy of therapeutic regimens for type 2 DM. CONCLUSIONS: The available data suggest using an earlier transition from monotherapy to combination therapy to minimize disease-associated morbidity. The availability of new insulin analogues has expanded therapeutic options and offers the potential to enhance the efficacy of therapeutic regimens for type 2 DM as well as improve the ease and safety of treatment when glycosylated hemoglobin cannot be maintained <7% on > or =1 oral antidiabetic agent.     

严重脓毒症患者胰岛素抵抗和胰岛素分泌功能的观察

目的探讨严重脓毒症患者入ICU后血糖、胰岛素浓度、胰岛素抵抗（IR）及胰岛素分泌功能的动态变化．与疾病的严重程度和预后的关系。方法选取严重脓毒症患者36例和正常对照20例,根据脓毒症后28d后的存活情况,分为生存组（n=20例）和死亡组（n=16）。回顾分析各组第1天、第28天空腹血糖（FBG）、胰岛素（FINS）浓度,使用稳态模式法（HOMA）计算胰岛素抵抗指数（HOMA—IR）及胰岛素分泌指数（HOMA-8）。结果严重脓毒症患者入组后第1天FBG、FINS浓度及HOMA—IR均明显高于对照组,HOMA—β明显低于对照组,差异均有统计学意义（t分别=7．46、5．64、7．07、6．73,P均〈0．05）。生存组与死亡组入组后第1天FBG、FINS浓度及HOMA—IR均高于对照组,而HOMA—β低于对照组,差异有统计学意义（t分别=5．13、4．43、5．49、4．70、6．85、3．60、5．02、8．96,P均〈0．05）;生存组第28天FBG、FINS浓度及HOMA—IR较第1天下降,而HOMA-β回升,差异均有统计学意义（t分别=3．71、2．72、4．06、2．47,P均〈0．05）;死亡组FBG和HOMA-IR高于生存组,HOMA—β低于生存组,差异有统计学意义（t分别=3．46、2．82、2．97,P均〈0．05）;而FINS浓度与生存组间差异无统计学意义（t=0．32,P〉0．05）。单个脏器功能不全患者FBG浓度、HOMA-β与对照组间比较,差异均无统计学意义（q分别=1．95、1．66,P均〉0．05）;多个脏器功能不全患者FBG、FINS浓度及HOMA—IR均高于对照组;而HOMA—β低于对照组,差异均有统计学意义（q分别=10．18、5．19、7．58、14．96,P均〈0．05）。APACHEⅡ评分与FBG、HOMA—IR呈正相关,与HOMA—β呈负相关,差异均有统计学意义（r分别=0．68、0．50、-0．66,P均〈0．05）。结论严重脓毒症患者存在IR,其中多脏器功能不全患者存在胰岛β细胞功能不全,FBG浓度、HOMA—IR及HOMA—β可作为判断严重脓毒症患者病情转归,预后的预警指标。     

Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes

OBJECTIVE: To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 58 diet-treated patients with type 2 diabetes (aged 54 +/- 1 years; 34 men and 24 women; BMI 31.5 +/- 0.6 kg/m(2)) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT). RESULTS: Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c (delta=-2.0 and -2.9%), FPG (delta=-66 and -97 mg/dl), and mean PG during OGTT (delta=-84 and -107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index (delta area under the curve [AUC] insulin/deltaAUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13 +/- 0.03 to 0.27 +/- 0.05, P < 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000/(square-root (FPG x FPI) x (PG x PI)) where PG and PI equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8 +/- 0.3 to 2.5 +/- 0.3, P < 0.05) or 45 mg (1.6 +/- 0.2 to 2.7 +/- 0.6, P < 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG x FPI)[k/(FPG x FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13 +/- 0.02 to 0.21 +/- 0.03, P < 0.05) and 45 mg (0.11 +/- 0.02 to 0.24 +/- 0.06, P < 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=-0.58), FPG (r=-0.47), mean PG during the OGTT (r=-0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed. CONCLUSIONS: Pioglitazone improves glycemic control through the dose-dependent enhancement of beta-cell function and improved whole-body and hepatic insulin sensitivity.