自发2型糖尿病模型OLETF大鼠肾周脂肪组织水通道蛋白7的表达

目的:观察自发2型糖尿病动物模型OLETF(Otsuka Long-Evans Tokushima Fatty)大鼠不同糖尿病病程阶段肾周脂肪组织水通道蛋白7 mRNA和蛋白表达的变化,探讨其在肥胖和糖尿病发生中的作用.方法:以OLETF大鼠30只为实验组,同种系非糖尿病LETO(Long-Evans Tokushima Otsuka)大鼠18只为正常对照.8周(基线)时两组大鼠各处死6只.随后OLETF大鼠分为末治疗组(OLETF组)12只及盐酸二甲双胍治疗组(OLETF/M组)12只.观察各组大鼠8、18、28周时的体重、血清甘油三酯、胆固醇、丙三醇、葡萄糖耐量试验的血糖与胰岛素水平以及肾周脂肪组织水通道蛋白7(aquaporin7,AQP7)mRNA和AQP7蛋白含量的变化.用Real-time PCR测定AQP7mRNA水平,Western blotting测定AQP7蛋白含量.结果:(1)OLETF组18周均发展为糖尿病[60分钟血糖(25.67±6.78)mmol/L,120分钟血糖(16.19±2.98)mmoL/L].OLETF组大鼠随周龄增加,其体重、血糖、胰岛素、血清甘油三酯均明显增加.血清丙三醇水平先增高后下降,8、18和28周的水平分别为(52.61±11.80)、(156.03±39.56)和(130.84±25.46)μmol/L.(2)OLETF/M组18周时达糖尿病标准[60分钟血糖(18.64±6.67)mmol/L,120分钟血糖(14.13±5.21)mmoL/L],但血糖水平低于OLETF组;28周时血糖下降均恢复为糖耐量异常[60分钟血糖(11.72 ±3.06)mmol/L,120分钟血糖(12.42±2.30)mmol/L].OLETF/M组的甘油三酯、胆固醇和丙三醇浓度较OLETF组降低.OLETF/M组与OLEFT组比较具体值为:甘油三酯18周(0.88±0.14)vs.(1.09 ±0.44)mmol/L,28周(1.06±0.51)vs.(2.20±1.51)mmol/L;胆同醇18周(2.18±0.14)vs.(2.30±0.21)mmol/L,28周(1.90±0.19)vs.(2.36±0.35)mmol/L,P<0.05;丙三醇18周(77.28±9.06)vs.(156.03±39.56)μmol/L,P<0.05,28周(58.44±14.03)vs.(130.84±25.46)μmol/L,P<0.01.(3)增加肾周脂肪组织AQP7 mRNA及蛋白表达:随周龄及肥胖增加,18及28周OLETF组AQP7 mRNA表达较同组8周龄大鼠分别上调了67.5%和41.7%,AQP7蛋白表达较同组8周龄大鼠分别上调了21.9%和8.9%;18及28周OLETF/M组AQP7 mRNA表达较同组8周龄大鼠分别上调了25%及8.3%,AQP7蛋白表达较同组8周龄大鼠分别上调了14.6%及1.6%.OLETF及OLETF/M组均呈先增高而后下降的趋势,于18周时增高,28周下降,与血清丙三醇变化趋势一致.OLETF/M组AQP7 mRNA及蛋白表达水平低于同周龄OLETF组,但两组差异无统计学意义.OLETF/M组的体重、胰岛素与OLETF组差异无统计学意义.OLETF/M组AQP7 mRNA及蛋白表达水平低于同周龄OLETF组,但两组差异无统计学意义.结论:内脏脂肪AQP7参与了糖脂代谢,与2型糖尿病和肥胖发病相关.二甲双胍可改善OLETF大鼠的脂代谢和糖代谢紊乱,但对AQP7 mRNA及蛋白表达未见明显影响.     

Increased intestinal glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in Otsuka Long-Evans Tokushima Fatty rats

Otsuka Long-Evans Tokushima Fatty (OLETF) rats are reported to be obese Type II (non-insulin-dependent) diabetic rats with insulin resistance and impaired insulin secretion. To investigate the contribution of intestinal glucose absorption to postprandial hyperglycaemia, we determined the plasma xylose concentrations after an 0.8 g/kg oral xylose load which was used as a test of small intestinal glucose absorption in 6-week-old OLETF rats and weight-matched Long-Evans Tokushima Otsuka (LETO) rats. An oral glucose tolerance test showed that OLETF rats developed hyperglycaemia at 60 and 90 min after the glucose load, though the fasting plasma glucose concentration, insulin concentration and insulin-induced in vivo glucose utilization rate were similar. Consistently, in an oral D-xylose loading test, the peak concentration of plasma xylose in OLETF rats was increased by 58.7% compared with that of LETO rats (p < 0.005). The disappearance rate of plasma xylose concentrations after intravenous xylose loading did not differ between the two strains. Co-treatment with 0.4 g/kg phlorizin, a specific inhibitor of sodium-dependent glucose transporter 1 (SGLT1), abolished both plasma glucose and xylose concentrations after the loads. Morphological studies showed that both the small intestinal wet weight and surface area were 30% larger in the OLETF rats than in the LETO rats. Furthermore, the SGLT1 mRNA content of OLETF rats also increased compared with LETO rats. These results suggest that an increased SGLT1 expression concomitant with intestinal hypertrophy in OLETF rats is partly associated with postprandial hyperglycaemia before the onset of insulin resistance and hyperinsulinaemia.     

Insulinoma in a patient with non-insulin-dependent diabetes mellitus

Insulinoma in a patient with pre-existing diabetes is exceedingly rare. Only a small number of well-documented cases have been reported in the world during the last 40 years. We describe a case with non-insulin-dependent diabetes mellitus who after seven years of sulfonylurea treatment experienced recurrent episodes of hypoglycemia. Endogenous hyperinsulinism was found and radiographical examination and transhepatic venous sampling confirmed an insulin secreting pancreatic tumor. After surgical excision of the tumor, patient was relieved from hypoglycemic attacks but required to initiate insulin injection for the treatment of hyperglycemia.     

Genetic dissection of "OLETF", a rat model for non-insulin-dependent diabetes mellitus

Granulation tissue formation was studied in viscose cellulose sponges with different cellulose contents and sizes after subcutaneous implantation in rats. Samples were removed and studied histologically and histomorphometrically 1-16 weeks after implantation. The implants with lower cellulose content and smaller size were invaded by more cells and filled with connective tissue more rapidly than those with the higher content and larger size. In larger sponge implants the beneficial effect of the lower cellulose content was more conspicuous.     

Effects of weight cycling and metabolic control in male outpatients with non-insulin-dependent diabetes mellitus.

Examined the effects of losing and regaining or gaining and relosing body weight in weight cycling (WC) vs weight maintenance (WM) on metabolic control. Ss were 327 adult male outpatient veterans (mean age 62.8 yrs) with non–insulin-dependent diabetes mellitus who were followed an average of 3.4 yrs. When compared with WM, WC, whether defined as a categorical or as a continuous variable, was not associated with deficits in metabolic control or increased need for hypoglycemic medication. Ss who weight cycled had fasting serum glucose and hemoglobin A1c levels comparable to those who remained within 10% of their initial body weights, and these levels of metabolic control were obtained with similar classes and dosages of hypoglycemic medication. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Frequency of diabetes in family members of probands with non-insulin-dependent diabetes mellitus

OBJECTIVES: To describe the prevalence of known diabetes in a multi-ethnic community in South Auckland, New Zealand, in relation to family history of diabetes and past history of diabetes in pregnancy. DESIGN: A cross-sectional, household survey comparing ascertainment with local general practice diabetes registers where they existed. SETTING: An inner-city community with a high proportion of Maori, Pacific Islands people and Europeans. SUBJECTS: A total of 55,518 residents (91% response). Comparison with diabetes registers showed 91% ascertainment of known diabetic residents. More detailed interviews with 176/214 (82%) Europeans, 286/336 (85%) Maori and 495/585 (85%) Pacific Islands people with known diabetes. Fifty subjects had insulin-dependent diabetes mellitus on clinical criteria and were excluded from analyses. MAIN OUTCOME MEASURES: Prevalence of diabetes. RESULTS: Those with non-insulin-dependent diabetes mellitus were more likely to have a diabetic mother than father (Europeans, 21.7% vs. 9.9%; Maori, 17.6 vs. 11.4%; Pacific Islands, 15.7 vs. 5.3%). Diabetic women had a similar likelihood of having a diabetic father as diabetic men but were 1.84 times as likely to have a diabetic mother (95% CI, 1.27-2.69). Diabetic women with past diabetes in pregnancy had 2.05 (95% CI, 1.01-4.15) times the chance of a diabetic offspring as women who had not had past diabetes in pregnancy, who in turn had 2.69 (95% CI, 1.17-6.18) times the likelihood of having a diabetic offspring as diabetic men. CONCLUSIONS: The mother is a more important conduit for inheritance of diabetes than the father in these three ethnic groups. A history of diabetes in pregnancy confers an extra risk to the offspring above this usual maternal excess.     

Breastfeeding and incidence of non-insulin-dependent diabetes mellitus in Pima Indians

BACKGROUND: Early exposure to cow's milk has been implicated in the occurrence of insulin-dependent diabetes mellitus but there is little information about infant-feeding practices and subsequent non-insulin-dependent diabetes mellitus (NIDDM). We examined the association between breastfeeding and NIDDM in a population with a high prevalence of this disorder, the Pima Indians. METHODS: Glucose-tolerance status was obtained from a 75 g oral glucose-tolerance test. A standard questionnaire given to mothers was used to classify infant-feeding practices for the first 2 months of life into three groups; exclusively breastfed, some breastfeeding, or exclusively bottlefed. The association between the three infant-feeding groups and NIDDM was analysed by multiple logistic regression. FINDINGS: Data were available for 720 Pima Indians aged between 10 and 39 years. 325 people who were exclusively bottlefed had significantly higher age-adjusted and sex-adjusted mean relative weights (146%) than 144 people who were exclusively breastfed (140%) or 251 people who had some breastfeeding (139%) (p = 0.019). People who were exclusively breastfed had significantly lower rates of NIDDM than those who were exclusively bottlefed in all age-groups (age 10-19, 0 of 56 vs 6 [3.6%] of 165; age 20-29, 5 [8.6%] of 58 vs 17 [14.7%] of 116]; age 30-39, 6 [20.0%] of 30 vs 13 [29.6%] of 44). The odds ratio for NIDDM in exclusively breastfed people, compared with those exclusively bottlefed, was 0.41 (95% CI 0.18-0.93) adjusted for age, sex, birthdate, parental diabetes, and birthweight. INTERPRETATION: Exclusive breastfeeding for the first 2 months of life is associated with a significantly lower rate of NIDDM in Pima indians. The increase in prevalence of diabetes in some populations may be due to the concomitant decrease in breastfeeding.     

The computer support of hypoglycemic therapy in non-insulin-dependent diabetes mellitus

Computer program designed by the authors and described in the article is realized as a reference system providing data on combinations of drugs used for diabetes mellitus. The system supplies information on hypoglycemic effects of representatives from each of three groups (insulins, sulfonamides, biguanides) administered both separately and in association with second drug selected by user. Interface of the system (drug menus and output windows) is friendly and demand no special training and operating skill. The program is written in C language and compiled as a single executable module for IBM-compatible personal computers.     

A risk-benefit appraisal of acarbose in the management of non-insulin-dependent diabetes mellitus

Acarbose is an alpha-glucosidase inhibitor proposed for the treatment of diabetic patients. It acts by competitively inhibiting the alpha-glucosidases in the intestinal brush border. The principal action of these enzymes is to convert nonabsorbable dietary starch and sucrose into absorbable monosaccharides (e.g. glucose). Enzyme inhibitors delay this conversion, slowing the formation and consequently the absorption of monosaccharides, and thus reducing the concentration of postprandial blood glucose. Both starch and sucrose are influenced, whereas lactose and glucose are not. Many studies in experimental animals, healthy volunteers and patients with non-insulin-dependent diabetes mellitus (NIDDM) have shown that acarbose decreases postprandial blood glucose, with a lesser reduction of fasting blood glucose, plasma triglycerides and postprandial insulin levels. In long term studies in NIDDM patients, acarbose significantly reduced glycosylated haemoglobin levels. Acarbose is only minimally absorbed from the gut and no systemic adverse effects have been demonstrated after long term administration. The drug allows undigested carbohydrates to pass into the large bowel where they are fermented causing flatulence, bloating and diarrhoea. These symptoms, which occur in approximately 30 to 60% of patients, tend to decrease with time and seem to be dose-dependent. They are minimised by starting therapy with low doses (such as 50mg 3 times daily) which may be effective in many patients. An increase in serum hepatic transaminases observed in earlier studies in the US, where doses of acarbose up to 900mg daily were used, has been not reported with the lower doses of the drug actually recommended [150 to 300mg (up to 600mg) daily]. In conclusion, acarbose may be useful in patients with NIDDM when diet alone is no longer able to maintain satisfactory blood glucose control. Furthermore, it may be a valid alternative to sulphonylurea or biguanide therapy when these drugs are contraindicated and insulin administration may be delayed. Acarbose seems also to be a useful adjunct to hypoglycaemic oral agents but its precise role in this field has not been fully clarified.     

Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus

Hyperproinsulinemia in non-insulin-dependent diabetes mellitus (NIDDM) is due to an increased release of proinsulin from pancreatic beta cells. This could reside in increased secretory demand placed on the beta cell by hyperglycemia or in the proinsulin conversion mechanism. In this study, biosynthesis of the proinsulin conversion enzymes (PC2, PC3, and carboxypeptidase-H [CP-H]) and proinsulin, were examined in islets isolated from 48-h infused rats with 50% (wt/vol) glucose (hyperglycemic, hyperinsulinemic, and increased pancreatic proinsulin to insulin ratio), 20% (wt/vol) glucose (normoglycemic but hyperinsulinemic), and 0.45% (wt/vol) saline (controls). A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed. This reduction did not correlate with any deficiency in mRNA levels or biosynthesis of PC2, PC3, CP-H, or proinsulin. Furthermore, proinsulin conversion rate was comparable in islets from hyperglycemic and control rats. However, in islets from hyperglycemic rats an abnormal increased proportion of proinsulin was secreted, that was accompanied by an augmented release of PC2, PC3 and CP-H. Stimulation of the beta cell's secretory pathway by hyperglycemia, resulted in proinsulin being prematurely secreted from islets before its conversion could be completed. Thus, hyperproinsulinemia induced by chronic hyperglycemia likely results from increased beta cell secretory demand, rather than a defect in the proinsulin processing enzymes per se.     

The antidyslipoproteinemic activity of ufibrate in patients with non-insulin-dependent diabetes mellitus

Ufibrate (150 mg daily) was found to have a beneficial effect on main parameters characterizing lipid metabolism, with no effect being exerted on carbohydrate metabolism, as evidenced by three months' follow-up of 24 patients aged 42 to 65 presenting with insulin-nondependent type II diabetes mellitus and hyperlipidemia. Ufibrate appeared to be a most efficacious long-term drug treatment option, particularly so in those patients presenting with initially high blood levels of a great many of lipid fractions.     

Beta-cell dysfunction in first-degree relatives of patients with non-insulin-dependent diabetes mellitus

To analyse the relationship between age, glucose tolerance, beta-cell function, and insulin sensitivity in preclinical states of non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), we have done a cross-sectional, age-stratified analysis of 86 non-diabetic first-degree relatives of NIDDM patients and 49 controls with similar age, sex, and BMI. A 5 mg kg ideal body weight-1 min-1 for 60 min of continuous infusion of glucose with model assessment (CIGMA) of serum glucose and C-peptide values at the end of the infusion was used to determine glucose tolerance and beta-cell function. Insulin sensitivity was estimated by modelling basal serum glucose and insulin values. Relatives and controls were divided into tertiles on the basis of age. Relatives had higher basal (5.3 vs 5 mmol l-1, p = 0.02) and achieved serum glucose (9.1 vs 8.4 mmol l-1, p = 0.01), lower beta-cell function (128 vs 145%, p = 0.007), and lower insulin sensitivity (37 vs 43%, p = 0.002). Beta-cell function declined with age in relatives (from 139% in young subjects to 134% in intermediate subjects and to 111% in older subjects, p = 0.002) and this decline was associated with an increase in basal serum glucose (from 5.1 to 5.3 and to 5.7 mmol l-1, p = 0.000) and achieved glucose (from 8.3 to 9.1 and to 9.3 mmol l-1, p = 0.038), without significant changes in insulin sensitivity. These trends were observed even after the exclusion of subjects with mild glucose intolerance. We conclude that both beta-cell dysfunction and insulin resistance are present in first-degree relatives of NIDDM. The progression of beta-cell dysfunction and glucose intolerance with age suggests that beta-cell dysfunction is the key factor in the apparition and progression of the disease.     

Endothelium-dependent relaxation in peripheral vasculature and kidney of non-insulin-dependent diabetes mellitus

Desmopressin (DDAVP), an AVP.V2-receptor agonist, evokes endothelium-dependent relaxation (EDR) due to nitric oxide (NO), EDR factor (EDRF) in the systemic vasculature, and glomerular afferent arterioles via AVP receptor(s). Glyceryl trinitrate (GTN) causes endothelium-independent (nonreceptor-mediated) vasodilation. We elucidated the possible involvement of EDRF in early non-insulin-dependent diabetes mellitus (NIDDM) and glomerular hyperfiltration (GHF) by DDAVP and GTN infusions. Patients with advanced DM nephropathy (DM.Np) (n = 7) were also examined. DDAVP and GTN decreased the mean blood pressure in DM with GHF (DM + GHF) and without GHF (DM-GHF) greater than that in normal subjects (N), without any difference in the heart rate changes in any group. Plasma levels of cGMP, a cellular messenger of NO, were significantly increased by DDAVP and GTN with a similar increment in each group. DDAVP caused a significant increase in urinary cGMP excretion in each group with a similar increment in each group. However, it caused a transient increase in creatinine clearance only in DM + GHF although GTN did not, and an exaggerated excretion of urinary albumin in early NIDDM, especially in DM+GHF, without a change in beta 2-microglobulin excretion. In contrast, in DM.Np GTN caused a decrease in blood pressure and an increase in plasma cGMP levels, but DDAVP did not. In conclusion, in peripheral vasculature and kidney, an enhanced sensitivity of vascular smooth muscle to NO is present in early NIDDM. The exaggerated dilation of glomerular afferent arterioles by preferentially produced NO in in situ, which causes a rise in PGC, might be partly responsible for the glomerular hyperfiltration and subsequently the increase in the glomerular protein permeation of DM+GHF. However, in peripheral blood vessels of DM.Np EDR is impaired. Thus, EDR seems to change with the development of NIDDM.     

Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)

The diagnostic criteria of the US National Diabetes Data Group and the World Health Organization have stimulated a major increase throughout the world in epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). They have established that much of NIDDM is undiagnosed, that onset of NIDDM occurs at least 7 y before its diagnosis, and that significant morbidity and premature mortality occur in subjects with undiagnosed diabetes. New studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of NIDDM as they move to urban or nontraditional situations, often with 5- to 10-fold increases in NIDDM prevalence. Epidemiologic studies have documented that major risk factors for NIDDM include increasing age, greater obesity, longer duration of obesity, unfavourable body fat distribution, physical inactivity, and hyperinsulinemia. All these factors interact with unknown genetic factors to produce NIDDM. Studies have shown that genes for diabetes, as yet undetermined, are a necessary cause of NIDDM. Hyperinsulinemia exists in childhood in populations at high risk for NIDDM. Stimulated by obesity, upper body obesity, and physical inactivity, insulin resistance develops, accompanied by impaired glucose tolerance. The pressure of the NIDDM risk factors continues this process of insulin resistance/hyperinsulinemia/hyperglycemia, until glucose toxicity to the beta cell results in inability to secrete sufficient insulin, resulting in decompensated fasting hyperglycemia.     

Predominance of a maternal history of diabetes for patients with non-insulin-dependent diabetes mellitus. Implications for the intrauterine transmission of diabetes

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by multiple congenital anomalies and mental retardation. SLOS has an associated defect in cholesterol biosynthesis, but the molecular genetic basis of this condition has not yet been elucidated. Previously our group reported a patient with a de novo balanced translocation [t(7;20)(q32.1;q13.2)] fitting the clinical and biochemical profile of SLOS. Employing fluorescence in situ hybridization (FISH), a 1.8 Mb chromosome 7-specific yeast artificial chromosome (YAC) was identified which spanned the translocation breakpoint in the reported patient. The following is an update of the on-going pursuit to physically and genetically map the region further, as well as the establishment of candidate genes in the 7q32.1 breakpoint region.     

Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse

Mice deficient in hepatocyte nuclear factor 1 alpha (HNF-1alpha) were produced by use of the Cre-loxP recombination system. HNF-1alpha-null mice are viable but sterile and exhibit a phenotype reminiscent of both Laron-type dwarfism and non-insulin-dependent diabetes mellitus (NIDDM). In contrast to an earlier HNF-1alpha-null mouse line that had been produced by use of standard gene disruption methodology (M. Pontoglio, J. Barra, M. Hadchouel, A. Doyen, C. Kress, J. P. Bach, C. Babinet, and M. Yaniv, Cell 84:575-585, 1996), these mice exhibited no increased mortality and only minimal renal dysfunction during the first 6 months of development. Both dwarfism and NIDDM are most likely due to the loss of expression of insulin-like growth factor I (IGF-I) and lower levels of insulin, resulting in stunted growth and elevated serum glucose levels, respectively. These results confirm the functional significance of the HNF-1alpha regulatory elements that had previously been shown to reside in the promoter regions of both the IGF-I and the insulin genes.