Overnight normalization of glucose concentrations improves hepatic but not extrahepatic insulin action in subjects with type 2 diabetes mellitus

Subjects with poorly controlled type 2 diabetes are both hyperglycemic and insulin resistant. To determine whether short term restoration of normoglycemia improves insulin action, hyperinsulinemic (approximately 300 pmol/L) euglycemic clamps were performed in diabetic subjects after either overnight infusion of saline or overnight infusion of insulin in amounts sufficient to maintain euglycemia throughout the night. Fasting glucose concentrations (5.2 +/- 0.2 vs. 11.9 +/- 1.4 mmol/L; P < 0.01) and rates of endogenous glucose production (13.0 +/- 1.1 vs. 18.6 +/- 1.6 mumol/kg.min; P < 0.05) were both lower after overnight insulin than overnight saline. Insulin-induced stimulation of glucose uptake (to 34.9 +/- 6.8 vs. 28.8 +/- 3.4 mumol/kg.min; P = 0.2) and inhibition of free fatty acids (to 0.13 +/- 0.03 vs. 0.12 +/- 0.04 mmol/L; P = 0.6) did not differ after overnight saline and overnight insulin. In contrast, endogenous glucose production during the final hour of the hyperinsulinemic clamps (i.e. when glucose concentrations were the same) remained higher (P = 0.05) after overnight saline than after overnight insulin (5.5 +/- 1.5 vs. 0.02 +/- 1.4 mumol/kg.min). Thus, acute restoration of euglycemia by means of an overnight insulin infusion improves hepatic (and perhaps renal) but not extrahepatic insulin action.     

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.     

Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin     

Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus

Recent epidemiological studies indicate that individuals who maintain a physically active lifestyle are much less likely to develop impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). Moreover, it was found that the protective effect of physical activity was strongest for individuals at highest risk of developing NIDDM. Reducing the risk of insulin resistance and NIDDM by regularly performed exercise is also supported by several aging studies. It has been found that older individuals who vigorously train on a regular basis exhibit a greater glucose tolerance and a lower insulin response to a glucose challenge than sedentary individuals of similar age and weight. While the evidence is substantial that aerobic exercise training can reduce the risk of impaired glucose tolerance and NIDDM, the evidence that exercise training is beneficial in the treatment of NIDDM is not particularly strong. Many of the early studies investigating the effects of exercise training on NIDDM could not demonstrate improvements in fasting plasma glucose and insulin levels, or glucose tolerance. The adequacy of the training programmes in many of these studies, however, is questionable. More recent studies using prolonged, vigorous exercise-training protocols have produced more favourable results. There are several important adaptations to exercise training that may be beneficial in the prevention and treatment of insulin resistance, impaired glucose tolerance and NIDDM. An increase in abdominal fat accumulation and loss of muscle mass are highly associated with the development of insulin resistance. Exercise training results in preferential loss of fat from the central regions of the body and should therefore contribute significantly in preventing or alleviating insulin resistance due to its development. Likewise, exercise training can prevent muscle atrophy and stimulate muscle development. Several months of weight training has been found to significantly lower the insulin response to a glucose challenge without affecting glucose tolerance, and to increase the rate of glucose clearance during a euglycaemic clamp. Muscle glucose uptake is equal to the product of the arteriovenous glucose difference and the rate of glucose delivery or muscle blood flow. While it has been known for many years that insulin will accelerate blood glucose extraction by insulin-sensitive peripheral tissues, recent evidence suggests that it can also acutely vasodilate skeletal muscle and increase muscle blood flow in a dose-dependent manner. A reduced ability of insulin to stimulate muscle blood flow is a characteristic of insulin-resistant obese individuals and individuals with NIDDM. Exercise training, however, has been found to help alleviate this problem, and substantially improve the control of insulin over blood glucose. Improvements in insulin resistance and glucose tolerance with exercise training are highly related to an increased skeletal muscle insulin action. This increased insulin action is associated with an increase in the insulin-regulatable glucose transporters, GLUT4, and enzymes responsible for the phosphorylation, storage and oxidation of glucose. Changes in muscle morphology may also be important following training. With exercise training there is an increase in the conversion of fast twitch glycolytic IIb fibres to fast twitch oxidative IIa fibres, as well as an increase in capillary density. IIa fibres have a greater capillary density and are more insulin-sensitive and -responsive than IIb fibres. Evidence has been provided that morphological changes in muscle, particularly the capillary density of the muscle, are associated with changes in fasting insulin levels and glucose tolerance. Furthermore, significant correlations between glucose clearance, muscle capillary density and fibre type have been found in humans during a euglycaemic clamp. Exercise training may also improve control over hepatic glucose production by increasin     

Regulation of hepatic glucose production in healthy subjects and patients with non-insulin-dependent diabetes mellitus

The regulation of endogenous glucose production is central to the control of blood glucose concentrations. In non-insulin-dependent diabetes mellitus (NIDDM), increased endogenous glucose production contributes to fasting hyperglycaemia. Gluconeogenesis appears to be exaggerated in NIDDM, and it may be hypothesized that an enhanced release of gluconeogenic precursors is responsible for increased total glucose output. However, it would appear that substrate-induced stimulation of gluconeogenesis fails to increase total glucose production in healthy humans and NIDDM patients. This autoregulation of endogenous glucose production may be attained by inhibition of glycogenolysis and/or gluconeogenesis from endogenous substrate. It has also been observed that stimulation of intrahepatic disposal of neoformed glucose (mainly as glycogen synthesis) contributes to autoregulation. These observations support the concept that intrahepatic disposal of glucose-6-phosphate plays a major role in the control of endogenous glucose production.     

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.     

The effect of postmenopausal estrogen therapy on the risk of non-insulin-dependent diabetes mellitus

OBJECTIVES: This study examined the effect of postmenopausal estrogen replacement therapy on the incidence of non-insulin-dependent diabetes in women. METHODS: Postmenopausal women aged 50 through 70 years (n=848) without diagnosed diabetes at baseline were followed for 10 to 15 years for incident diabestes. RESULTS: Over the average 11.5 year follow-ip, there were 105 new cases of diabetes. The age-adjusted relative-risk for development of diabetes was nonsignificantly lower for women with continuous estrogen replacement therapy use than for never users. After adjustment for major covariates, a nonsignificant linear trend with increasing duration of estrogen replacement therapy was reversed. CONCLUSIONS: This study suggests that previous results showing a reduced risk of diabetes in women using estrogen may have been due to selection bias regarding who is prescribed estrogen, confounding factors, or differential diagnostic efforts.     

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.     

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 association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort

This is the first demonstration of the use of accelerator mass spectrometry (AMS) as a tool for the measurement of 3H with attomole (10(-18) mol) sensitivity in a biological study. AMS is an analytical technique for quantifying rare isotopes with high sensitivity and precision and has been most commonly used to measure 14C in both the geosciences and more recently in biomedical research. AMS measurement of serially diluted samples containing a 3H-labeled tracer showed a strong correlation with liquid scintillation counting. The mean coefficient of variation of 3H AMS based upon the analysis of separately prepared aliquots of these samples was 12%. The sensitivity for 3H detection in tissue, protein, and DNA was approximately 2-4 amol/mg of sample. This high sensitivity is comparable to detection limits for 14C-labeled carcinogens using 14C AMS and demonstrates the feasibility of 3H AMS for biomedical studies. One application of this technique is in low-dose, dual-isotope studies in conjunction with 14C AMS. We measured the levels of 3H-labeled 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 14C-labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in rat liver tissue and bound to liver DNA and protein 4.5 h following acute administration of individual or coadministered doses in the range of 4-5100 pmol/kg of body weight. Levels of PhIP and MeIQx in whole tissue and bound to liver protein were dose-dependent. MeIQx-protein and -DNA adduct levels were higher than PhIP adduct levels, which is consistent with their respective carcinogenicity in this organ. Coadministration of PhIP and MeIQx did not demonstrate any measurable synergistic effects compared to administration of these compounds individually. These studies demonstrate the application of AMS for the low-level detection of 3H in small biological samples and for its use in conjunction with 14C AMS for dual-labeling studies.     

The esters of carboxylic nutrients as insulinotropic tools in non-insulin-dependent diabetes mellitus

1. In non-insulin-dependent diabetes mellitus, the pancreatic B-cell displays a preferential impairment of its secretory response to D-glucose. 2. A number of agents could be used to restore secretory activity in the diseased B-cell. 3. In this respect, esters of carboxylic nutrients, such as succinic or glutamic acid, present the advantages of stimulating both proinsulin biosynthesis and insulin release, remaining efficient in models of B-cell glucotoxicity, augmenting the secretory response to hypoglycemic pharmacological agents, protecting the B-cell against cytotoxic aggressions, and exerting a long-term beneficial effect upon the secretory potential of the endocrine pancreas. 4. Potential limitations of this new therapeutical approach, such as the generation of methanol from the esters, their postulated inefficacy after enteral administration, or the occurrence of extrapancreatic metabolic effects may be circumvented. 5. The esters of carboxylic nutrients could even be used in other cells endangered by ATP depletion.     

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.     

Tumor necrosis factor-alpha; a possible pathogenic factor in obesity in insulin resistant and non-insulin-dependent diabetes mellitus?

The role of tumor necrosis factor (TNF)-alpha in the development of insulin resistance has repeatedly been emphasized in the past few years. The present paper summarizes the data (including the authors' observations as well) focusing on the potential role of TNF-alpha in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus: alteration of insulin receptor function, lipid metabolism, expression of sulphonylurea receptors, all of them suggested to be related to the TNF-alpha. The potential clinical relevances are shortly reviewed.     

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.     

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.     

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.     

Altered action of angiotensin II in patients with type 2 diabetes mellitus of recent onset

Two studies, designed to mimic a single-dose, cross-over pharmacokinetic protocol, were conducted to gain a better understanding of the rat's response to multiple, frequent blood sampling. Parameters evaluated included body weight, clinical signs of disease, hematologic and serum biochemical analytes, organ weights, and histopathologic features. Study groups consisted of either 6 or 8 male, viral antibody-free, Sprague Dawley rats. These included controls and blood-collection groups that represented withdrawal of 10, 15, 20, 30, and 40% of estimated total blood volume. Volume of blood collected per time point was based on the total volume to be withdrawn divided by the 13 samples that were collected over 24 h. This regimen was repeated 2 weeks later. Samples were taken for clinical pathologic evaluation on the days subsequent to blood collection for both studies as follows: 0, 1, 2, and 3 days; 7, 8, or 9 days; and either 13 or 14 days. In Study 1, samples were also taken on either days 15 or 16, and on 17 or 18 after the second blood collection. Approximately 2 weeks after the second blood collection regimen, animals were euthanized. Animals in one study were necropsied, and selected tissues were taken for histologic examination. Analysis of variance, based on changes from baseline, was used to assess group differences. Results indicate that the rate of body-weight gain for the bled groups was not significantly different from that of the controls. Group differences in multiple hematologic parameters were significant. Changes were typical of acute blood-loss anemia, with positive or negative trends relating to the volume of blood removed. In addition, these changes were characterized by recovery to control values within approximately 14 days. Few statistically significant group differences were detected in serum biochemical values, and those detected were not biologically relevant. Although organ weights of bled groups were similar to those of controls, minimal to mild splenic hematopoiesis was present in all bled groups, compared with controls. These data indicate that removal of up to 40% of a rat's total blood volume over a 24-h period, and repeated 2 weeks later, caused no gross ill effects.