No effects of pantoprazole on the pharmacokinetics of rosuvastatin in healthy subjects.

PURPOSE: Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin. METHODS: The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine. RESULTS: Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91-1.16]), AUC0-∞ (1.03 [0.89-1.19]) and renal clearance (0.96 [0.85-1.09]) were all within the pre-specified range of 0.8-1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin. CONCLUSIONS: Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Glycaemic control and self-management behaviours in Type 2 diabetes: results from a 1-year longitudinal cohort study.

AIM: To better understand the associations between changes in self-management behaviours and glycaemic control. METHODS: We conducted a prospective observational study of 295 adult patients with Type 2 diabetes evaluated at baseline, 6 and 12 months. Four self-management behaviours were evaluated using the Summary of Diabetes Self-Care Activities instrument, which assesses healthy diet, physical activity, medication taking and self-monitoring of blood glucose. Using hierarchical linear regression models, we tested whether changes in self-management behaviours were associated with short-term (6-month) or long-term (12-month) changes in glycaemic control, after controlling for demographic and clinical characteristics. RESULTS: Improved diet was associated with a decrease in HbA1c level, both at 6 and 12 months. Improved medication taking was associated with short-term improvement in glycaemic control, while increased self-monitoring of blood glucose frequency was associated with a 12-month improvement in HbA1c . Completely stopping exercise after being physically active at baseline was associated with a rise in HbA1c level at 6-month follow-up. Interaction analysis indicated that a healthy diet benefitted all participant subgroups, but that medication taking was associated with glycaemic control only for participants living in poverty and more strongly for those with lower educational levels. Finally, a higher self-monitoring of blood glucose frequency was associated with better glycaemic control only in insulin-treated participants. CONCLUSIONS: Even after adjusting for potential confounders (including baseline HbA1c ), increased frequency of healthy diet, medication taking and self-monitoring of blood glucose were associated with improved HbA1c levels. These self-management behaviours should be regularly monitored to identify patients at risk of deterioration in glycaemic control. Barriers to optimum self-management should be removed, particularly among socio-economically disadvantaged populations.

Altering source or amount of dietary carbohydrate has acute and chronic effects on postprandial glucose and triglycerides in type 2 diabetes: Canadian trial of Carbohydrates in Diabetes (CCD).

BACKGROUND AND AIMS: Nutrition recommendations for type 2 diabetes (T2DM) are partly guided by the postprandial responses elicited by diets varying in carbohydrate (CHO). We aimed to explore whether long-term changes in postprandial responses on low-glycemic-index (GI) or low-CHO diets were due to acute or chronic effects in T2DM. METHODS AND RESULTS: Subjects with diet-alone-treated T2DM were randomly assigned to high-CHO/high-GI (H), high-CHO/low-GI (L), or low-CHO/high-monounsaturated-fat (M) diets for 12-months. At week-0 (Baseline) postprandial responses after H-meals (55% CHO, GI = 61) were measured from 0800 h to 1600 h. After 12 mo subjects were randomly assigned to H-meals or study diet meals (L, 57% CHO, GI = 50; M, 44% CHO, GI = 61). This yielded 5 groups: H diet with H-meals (HH, n = 34); L diet with H- (LH, n = 17) or L-meals (LL, n = 16); and M diet with H- (MH, n = 18) or M meals (MM, n = 19). Postprandial glucose fluctuations were lower in LL than all other groups (p < 0.001). Changes in postprandial-triglycerides differed among groups (p < 0.001). After 12 mo in HH and MM both fasting- and postprandial-triglycerides were similar to Baseline while in MH postprandial-triglycerides were significantly higher than at Baseline (p = 0.028). In LH, triglycerides were consistently (0.18-0.34 mmol/L) higher than Baseline throughout the day, while in LL the difference from Baseline varied across the day from 0.04 to 0.36 mmol/L (p < 0.001). CONCLUSION: Low-GI and low-CHO diets have both acute and chronic effects on postprandial glucose and triglycerides in T2DM subjects. Thus, the composition of the acute test-meal and the habitual diet should be considered when interpreting the nutritional implications of different postprandial responses.

Long-term effect of rosiglitazone and/or ramipril on the incidence of diabetes.

AIMS/HYPOTHESIS: The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial reported that 3 years of therapy with rosiglitazone reduced the primary outcome of diabetes or death by 60%. Here we investigated whether an effect on diabetes prevention persists more than 1.5 years after therapy has been discontinued. METHODS: The DREAM On passive follow-up study was conducted at 49 of the 191 DREAM sites. Consenting participants were invited to have a repeat OGTT 1-2 years after active therapy ended. A diagnosis of diabetes at that time was based on either a fasting or 2 h plasma glucose level of ≥7.0 mmol/l or ≥11.1 mmol/l, respectively, or a confirmed diagnosis by a non-study physician. Regression to normoglycaemia was defined as a fasting and 2 h plasma glucose level of <6.1 mmol/l and <7.8 mmol/l, respectively. RESULTS: After a median of 1.6 years after the end of the trial and 4.3 years after randomisation, rosiglitazone participants had a 39% lower incidence of the primary outcome (hazard ratio [HR] 0.61, 95% CI 0.53-0.70; p < 0.0001) and 17% more regression to normoglycaemia (95% CI 1.01-1.34; p = 0.034). When the analysis was restricted to the passive follow-up period, a similar incidence of both the primary outcome and regression was observed in people from both treatment groups (HR 1.00, 95% CI 0.81-1.24 and HR 1.14, 95% CI 0.97-1.32, respectively). Similar effects were noted when new diabetes was analysed separately from death. Ramipril did not have any significant long-term effect. CONCLUSIONS/INTERPRETATION: Time-limited exposure to rosiglitazone reduces the longer term incidence of diabetes by delaying but not reversing the underlying disease process.

No relationship between mean plasma glucose and glycated haemoglobin in patients with cystic fibrosis-related diabetes.

AIM: Cystic fibrosis-related diabetes (CFRD) prevalence has increased dramatically with the improved life expectancy of patients with cystic fibrosis (CF). Glycated haemoglobin (HbA(1c)) is an important tool for monitoring blood glucose control but, unlike in type 1 and type 2 diabetes, a correlation between HbA(1c), fructosamine and mean plasma glucose has not been clearly established in CF. This study aimed to examine the relationship between mean plasma glucose and HbA(1c) or fructosamine in stable patients with CFRD. METHODS: Fifteen type 1 diabetes and 13 CFRD patients (HbA(1c)<9.0%; no anaemia), matched for age and body mass index (BMI), provided 72 capillary blood glucose profiles taken 3days/month for three months. At the end of this time, HbA(1c) and fructosamine were measured. Mean plasma glucose was estimated using the Diabetes Control and Complications Trial (DCCT) conversion formula, and linear regressions carried out to establish its relationship with HbA(1c) and fructosamine. RESULTS: In type 1 diabetes patients, mean plasma glucose correlated significantly with HbA(1c) (r=0.68; P=0.005). In CFRD patients, no correlation was found between mean plasma glucose and HbA(1c) (r=0.24; P=0.460). Also, no association was found between mean plasma glucose, representing the month before blood sampling, and fructosamine in either group. CONCLUSION: Unlike in type 1 diabetes, HbA(1c) did not correlate with mean plasma glucose in CFRD subjects. Thus, having a normal HbA(1c) may not be sufficient to indicate a low risk of diabetes complications in CFRD. Further studies are required to explain such a discrepancy.

Effect of glucagon on glucose production during insulin deficiency in the dog.

The aim of the present experiments was to determine the effects of basal glucagon on glucose production after induction of prolonged insulin lack in normal conscious dogs fasted overnight. A selective deficiency of insulin or a combined deficiency of both pancreatic hormones was created by infusing somatostatin alone or in combination with an intraportal replacement infusion of glucagon. Glucose production (GP) was measured by a primed constant infusion of [3H-3]glucose, and gluconeogenesis (GNG) was assessed by determining the conversion rate of circulating [14C]alanine and [14C]lactate into [14C]glucose. When insulin deficiency was induced in the presence of basal glucagon the latter hormone caused GP to double and then to decline so that after 4 h it had returned to the conrol rate. The conversion of alanine and lactate into glucose, on the other hand, increased throughout the period of insulin lack. Withdrawal of glucagon after GP had normalized resulted in a 40% fall in GP, a 37% decrease in GNG, and a marked decrease in the plasma glucose concentration. Induction of insulin deficiency in the absence of basal glucagon resulted in an initial (30%) drop in GP followed by a restoration of normal GP after 2--3 h and moderately enhanced glucose formation from alanine and lactate. It can be concluded that (a) the effect of relative hyperglucagonemia on GP is short-lived; (b) the waning of the effect of glucagon is attributable solely to a diminution of glycogenolysis because GNG remains stimulated; (c) basal glucagon markedly enhances the GNG stimulation apparent after induction of insulin deficiency; and (d) basal glucagon worsens the hyperglycemia pursuant on the induction of insulin deficiency both by triggering an initial overproduction of glucose and by maintaining the basal production rate thereafter.

Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle.

The effect of epinephrine on basal and insulin-stimulated glucose uptake in perfused hindlimbs of fed rats was studied. Insulin increased glucose uptake in a dose-dependent manner from a basal value of 1.5+/-0.3 up to a maximum value of 5.3+/-0.9 mumol/min per 100 g with 6 nM (1 m U/ml). Epinephrine at 10 nM and 0.1 muM also increased glucose uptake to 2.6+/-0.1 and 3.1+/-0.1 mumol/min per 100 g, respectively. These same concentrations of epinephrine, however, suppressed the insulin-stimulated glucose uptake to 3.2+/-0.3 mumol/min per 100 g. Both the stimulatory and inhibitory effects of epinephrine on glucose uptake were completely reversed by propranolol, but were not significantly altered by phentolamine. Uptake of 3-O-methylglucose and 2-deoxyglucose into thigh muscles of the perfused hindlimbs was stimulated fivefold by insulin, but was unaffected by epinephrine. Epinephrine also did not inhibit the stimulation of uptake by insulin. Epinephrine decreased the phosphorylation of 2-deoxyglucose, however, and caused the intracellular accumulation of free glucose. These last two effects were more prominent in the presence of insulin. Whereas epinephrine caused large rises in glucose-6-P and fructose-6-P, insulin did not alter the concentration of these metabolites either in the absence or presence of epinephrine.THESE DATA INDICATE THAT: (a) epinephrine has a stimulatory effect on glucose uptake by perfused rat hindlimbs that does not appear to be exerted on skeletal muscle; (b) epinephrine does not affect hexose transport in skeletal muscle; (c) epinephrine inhibits insulin-stimulated glucose uptake in skeletal muscle by inhibiting glucose phosphorylation. It is hypothesized that the inhibition of glucose phosphorylation is due to the stimulation of glycogenolysis, which leads to the accumulation of hexose phosphates, which inhibit hexokinase.

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusin somatostatin (1 mug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+/-6 and 81+/-8%, respectively. Intraportal infusion of insulin and glucagon at rates of 400 muU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques. Isolated glucagon deficiency resulted in a 35+/-5% (P less than 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration of the plasma glucagon level. Isolated insulin deficiency resulted in a 52+/-16% (P less than 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. In conclusion, in the anesthetized dog fasted overnight; (a) basal glucagon is responsible for at least one-third of basal glucose production, (b) basal insulin prevents the increased glucose production which would result from the unrestrained action of glucagon, and (c) somatostatin has no acute effects on glucose turnover other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important in the regulation of basal glucose production in the postabsorptive state.

Normal adiponectin levels despite abnormal glucose tolerance (or diabetes) and inflammation in adult patients with cystic fibrosis.

RATIONALE: Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity. Since these conditions are common in cystic fibrosis (CF), we examined whether adiponectin values are altered in these patients. AIM: To determine if CF patients have altered adiponectin levels and if these levels correlate with glucose tolerance categories (normal, impaired glucose tolerance (IGT) and cystic fibrosis-related diabetes (CFRD)), insulin resistance or inflammatory markers such as fibrinogen and C-reactive protein (CRP). METHODS: Oral glucose tolerance tests (OGTTs) were performed and adiponectin levels were measured in 90 CF patients not known to be diabetic and 15 healthy controls matched for age, sex and body mass index (BMI). Inflammatory markers, serum albumin concentrations and the clinical status of CF patients (i.e. pulmonary function) were also examined. RESULTS: CF pathology was characterized by a high prevalence (43.5%) of glucose tolerance abnormalities: 26.5% of IGT and 17.0% of newly diagnosed CFRD. CF patients also presented systemic inflammation as revealed by a significant increase of fibrinogen (P=0.029) in all patients and higher CRP levels in CFRD patients compared to the controls (P<0.05). On the other hand, CF and control subjects had similar albumin serum concentration. While CF patients and controls had similar serum adiponectin values, women had significantly higher hormone levels than men (P<0.001). Adiponectin levels did not correlate with glucose tolerance, inflammatory markers or insulin resistance. On the other hand, they correlated positively with both total and HDL-cholesterol (P<0.001). CONCLUSION: CF patients did not show any alterations in adiponectin levels despite insulin resistance, glucose intolerance and sub clinical chronic inflammation. Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident.

Postprandial hyperglycaemia: to treat or not to treat?

Accumulating evidence suggests that the postprandial or the post-75 g glucose load rise in plasma glucose are a contributing factor to the development of atherosclerosis. Many epidemiological studies have shown that post-load hyperglycaemia is a strong and independent risk factor for cardiovascular disease. The few interventional studies available also support a role for postprandial or post-load hyperglycaemia on cardiovascular disease or mortality or on validated surrogates of atherosclerosis. The mechanism through which acute hyperglycaemia could exert its deleterious effects on the vessel wall is very likely multifactorial, but the overproduction of free radicals is probably involved. There is growing evidence that treating postprandial hyperglycaemia should probably be part of the strategies for the prevention and management of cardiovascular diseases in pre-diabetes as well as in diabetes.

Comparative characterization of receptor and non-receptor associated protein tyrosine kinases.

By using poly(Glu: Tyr, 4:1) as an exogenous substrate, the characteristics of insulin receptor associated protein tyrosine kinase (PTK) from rabbit skeletal muscle has been compared with a growth factor-independent non-receptor PTK partially purified from rat lung particulate fraction. The two PTKs phosphorylated poly(Glu: Tyr; 4:1) very effectively with apparent Km values of 0.3 mg/ml for insulin receptor PTK and 0.8 mg/ml for lung PTK. ATP was the preferred phosphoryl donor for both PTKs (Km = 150 microM); however, in the case of lung PTK, GTP was able to partially replace ATP. ATP analogues, AMP-PNP and ATP-gamma-S inhibited the activities of both enzymes. Receptor PTK was more active in the presence of Mn2+ whereas the lung PTK did not discriminate between Mg2+ or Mn2+ for enzyme activity. Para-hydroxymercurobenzoate (pHMB), a SH-group blocking agent, inhibited the activities of both PTKs, suggesting the requirement of SH-groups for enzymatic activities. Both enzymes were inhibited by fluorosulfonylbenzoyl 5'-adenosine (FSBA). NaCl also inhibited both kinases, however, lung PTK was more sensitive to inhibition. In addition, the lung PTK was not retained on a wheat germ agglutinin (WGA)-agarose column, suggesting that the lung enzyme is either not a glycoprotein or that the carbohydrate moieties present, if any, have no affinity for WGA. Furthermore, the lung PTK appears to be immunologically distinct from both insulin receptor and pp60Src, since it was not immunoprecipitated by antibodies to either pp60Src or insulin receptor. These data indicate that only a few but significant differences exist in the characteristics of receptor and non-receptor associated PTKs.

Prevention of type 2 diabetes: insulin resistance and beta-cell function.

Type 2 diabetes is increasing worldwide in epidemic proportions. Its associated morbidity and mortality is imposing a major burden on the health care system. Based on a better understanding of the pathophysiology of glucose intolerance, clinical trials on the prevention of diabetes have been performed. It has now been demonstrated that diet and exercise, metformin, acarbose, and troglitazone can prevent or at least delay the development of diabetes in subjects with impaired glucose tolerance (IGT). It is now generally accepted that insulin resistance and beta-cell dysfunction are major factors involved in the development of diabetes. The relative contribution of insulin resistance versus beta-cell dysfunction on the pathogenesis of diabetes has aroused much debate. These two processes should be studied in relation to one another: their relationship is best described as hyperbolic in nature. When this relationship is taken into consideration, it becomes evident that subjects at risk of developing type 2 diabetes have beta-cell dysfunction before they develop glucose intolerance. Insulin resistance may be mostly explained by the presence of obesity and accelerate the progression to diabetes in subjects with the propensity to beta-cell failure. By the time hyperglycemia occurs, impairment in both insulin sensitivity and insulin secretion are present. There are still few data on insulin sensitivity and insulin secretion from the trials on the prevention of diabetes. The few data that we do have suggest that most interventions mostly have an effect on insulin resistance. By reducing insulin resistance, they protect and preserve the beta-cell function. No intervention has yet shown any direct effect on beta-cell function.

Therapeutic modulation of growth-promoting activity in platelets from diabetics.

Proliferation of vascular smooth muscle is thought to be involved in the major diabetic complication atherosclerosis. We have previously reported an increase of growth-promoting activity (GA) in platelets from insulin-dependent diabetics. In this study, GA was measured in the platelet extract (PE) from eight diabetic patients who had been treated by conventional insulin therapy. Vascular smooth muscle cells from rat aorta were cultured and used as an assay system for GA. Incorporation of [3H]thymidine into DNA of cultured cells was stimulated by diabetic PE significantly more (P less than .05) than by normal PE. Diabetic PE incubated with cells for 4 days increased cell numbers significantly more (P less than .05) than normal PE. These abnormalities were corrected by long-term intensive insulin treatments (continuous subcutaneous insulin infusion and Pen infuser). The decrease of platelet extract GA appeared to correlate with the amount of insulin administered before meals as short-acting boluses, whereas the level of basal or long-acting insulin appeared to correlate with an increase of PE GA. Thus, the growth-promoting potential of platelets can be normalized by intensive insulin therapy. The relationship of insulin levels to this activity needs further evaluation.

Insulin lispro in CSII: results of a double-blind crossover study.

Insulin lispro is a human insulin analog that dissociates more rapidly than human regular insulin after subcutaneous injection, resulting in higher insulin levels at an earlier point in time and a shorter duration of action. The aim of the study was to evaluate if this pharmacokinetic difference would translate into better postprandial and overall control in 30 IDDM patients (age, 35.1 +/- 1.5 years; male-female ratio, 17:13; BMI, 24.8 +/- 0.5 kg/m2; HbA1c, 8.03 +/- 0.13% at baseline) treated with continuous subcutaneous insulin infusion (CSII; Disetronic H-TRON V100) in a double-blind crossover clinical study. Patients were randomized to insulin lispro or human regular insulin for 3 months before crossing over to the other insulin for another 3 months. All meal boluses were given immediately before breakfast, lunch, and supper. An eight-point blood glucose profile was measured once weekly, and HbA1c levels were measured monthly. At the end of the 3-month treatment period, HbA1c levels were significantly lower with insulin lispro, compared with human regular insulin: 7.66 +/- 0.13 vs. 8.00 +/- 0.16% (P = 0.0041). While preprandial, bedtime, and 2:00 A.M. values for blood glucose were not significantly different, 1-h postprandial blood glucose was significantly improved after breakfast, lunch, and dinner with insulin lispro, compared with human regular insulin: 8.35 vs. 9.79 mmol/l (P = 0.006), 7.58 vs. 8.74 mmol/l (P = 0.049), and 7.85 vs. 9.01 mmol/l (P = 0.03). The incidence of hypoglycemia per 30 days (blood glucose levels, <3.0 mmol/l) was 8.4 +/- 1.3 before randomization, decreasing to 6.0 +/- 0.9 for insulin lispro and to 7.6 +/- 1.3 for regular insulin during the last month of the study. Two patients in each group reported insulin precipitation. We conclude that insulin lispro improves glycemic control in CSII without increasing the risk of hypoglycemia.

Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs.

The suppressive effect of insulin on hepatic glucose production is generally recognized. Though it is well established that this effect is at least partially due to inhibition of glycogenolysis, controversy still exists about insulin's effect on gluconeogenesis. The present study was undertaken to determine whether insulin could affect gluconeogenesis from alanine in the intact dog and to compare the effect of insulin on glycogenolysis and gluconeogenesis. In anesthetized dogs fasted overnight, blood samples were drawn simultaneously from a femoral artery and hepatic vein. Alanine-U-14C, 10 mu Ci./kg., was infused over 110 minutes. A constant insulin infusion at either 1 or 5 mU./kg./min. was begun at 50 minutes, and blood glucose concentration was maintained by a variable glucose infusion. When insulin was infused at 1 mU./kg./min., resulting in plasma immunoreactive insulin (IRI) levels of 73 +/- 10 muU./ml., the net splanchnic glucose production (NSGP) was suppressed from 2.7 +/- 2 mg./kg./min. to virtually zero. In constrast, this small increment in insulin concentration had no demonstrable effect on the net splanchnic uptake of alanine or on the conversion of plasma alanine to glucose (7.9 +/- 0.3 mu mol/min.). Insulin infused at 5 mU./kg./min. resulted in IRI levels of 240 +/- 25 muU./ml. This higher insulin concentration was associated with a marked suppression of both the NSGP (100 per cent) and the conversion of plasma alanine to glucose (90 per cent) but did not affect the extraction of alanine by the splanchnic bed. Doses of both 1 and 5 mU./kg./min. were associated with a 35 per cent fall in immunoreactive glucagon levels. These data demonstrate that (1) glycogenolysis is more sensitive than gluconeogenesis to the inhibitory effect of small increments in insulin concentrations, (2) gluconeogenesis could be suppressed by insulin but only at higher insulin concentrations, (3) this suppression of gluconeogenesis from alanine by insulin was due to an intrahepatic effect rather than an effect on the splanchnic extraction of alanine, and finally, (4) that insulin can suppress glucagon in the absence of hyperglycemia.

Gluconeogenesis from alanine in normal postabsorptive man. Intrahepatic stimulatory effect of glucagon.

Although the stimulatory effect of glucagon on gluconeogenesis has been well demonstrated in certain systems in vitro, this effect has never been established in man. The present study was undertaken, therefore, to determine whether glucagon could stimulate gluconeogenesis from alanine in normal fasting man. Glucagon might stimulate this process by increasing the hepatic alanine uptake and/or by shunting the extracted alanine within the liver into the gluconeogenic pathway. In order to be able to examine these two aspects of gluconeogenesis, we combined the hepatic vein-brachial artery catheterization technic with an istopic infusion of alanine-14C. Alanine-14C specific activity was measured in whole blood and plasma by use of a rapid chromatographic technic. Since plasma contributed 93 per cent of the alanine extracted by the splanchnic bed with a specific activity three times that of the red blood cells, plasma alanine specific activity was used to study the conversion of alanine to glucose. A constant infusion of alanine-14C achieved a relatively stable arterial specific activity by forty minutes. The administration of glucagon by constant infusion (15-50 ng./kg./min.) had no affect on thf splanchnic extraction of alanine. Net splanchnic glucose-14C production, however, doubled during the glucagon infusion, and the conversion of alanine to glucose increased from 30 plus or minus 2 to 58 plus or minus 9 mumol/min. These data (1) demonstrate that in normal man fasted twelve to fourteen hours, glucagon at supraphysiologic levels can double the rate of gluconeogenesis from alanine and (2) indicate that this stimulatory effect of glucagon is exerted within the liver by shunting the extracted alanine toward new glucose formation rather than by increasing the hepatic extraction of alanine.

The prevention of type 2 diabetes: what is the evidence?

The prevalence of diabetes is increasing in epidemic proportion worldwide. Because of the morbidity and mortality associated with the disease, it is becoming a major burden for the health care system. With a better understanding of the pathogenesis of type 2 diabetes, the concept of primary prevention has emerged. A number of studies demonstrated that both lifestyle modification program and pharmacological interventions in subjects with impaired glucose tolerance (IGT) can prevent or delay the progression to diabetes. The Diabetes Prevention Study (DPS) and the Diabetes Prevention Program (DPP) convincingly showed that an intensive lifestyle modification program is highly effective in decreasing the risk of diabetes in a high risk population (risk reduction of 58%). Four other smaller studies have made similar observations. The DPP study showed that metformin can reduced the risk of diabetes by 31% in subjects with IGT. The STOP-NIDDM trial confirmed the efficacy of acarbose in decreasing the risk of diabetes by 36% in similar high risk population. The TRIPOD study showed that troglitazone can reduce the incidence of diabetes by 55% in Hispanic women with a history of gestational diabetes. And more recently, the XENDOS study showed that in very obese population on intensive lifestyle modification program, xenical treatment was associated with a 37% reduced incidence of diabetes compared to placebo. Three studies suggested that bariatric surgery in morbidly obese subjects with or without IGT can reduce the incidence of diabetes to near zero. Eight of 10 studies showed that treatment with inhibitors of the renin-angiotensin aldosterone system in high risk population for cardiovascular disease (CVD) were associated with a significant reduction in the subsequent development of diabetes as a secondary outcome. The WOSCOPS study and the HERS study examined the effect of pravastatin and estrogen/progestin respectively on cardiovascular events and observed that these pharmacological interventions were associated with a 30% and 35% reduction in the incidence of diabetes as secondary outcome. There are 3 major trials currently in progress examining the effect of rosiglitazone/ramipril (the DREAM study), nateglinide/valsartan (the NAVIGATOR study) and pioglitazone (the ACT NOW study) on the development of diabetes in IGT subjects as a primary outcome. We also have 3 studies studying the prevention of diabetes as secondary outcomes: the ONTARGET-TRANSCEND study examining telmisartan with or without ramipril, and the ORIGIN study testing glargine insulin/omega 3. The evidence is overwelming-diabetes can be prevented or delayed in high risk population through lifestyle modification or pharmacological interventions. This new information now has to be translated in the real world into well defined strategies for screening and treating high risk population. Prevention of the disease is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.

The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes.

OBJECTIVE: To investigate the efficacy and safety of miglitol in combination with metformin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently controlled by diet alone. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind, placebo-controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA(1c) from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate. RESULTS: A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean placebo-subtracted HbA(1c) of -1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (-1.25; P = 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone for fasting plasma glucose (-44.8 vs. -20.4 mg/dl; P = 0.0025), 2-h postprandial glucose area under the curve (-59.0 vs. -18.0 mg/dl; P = 0.0001), and responder rate (70.6 vs. 45.52%; P = 0.0014). All therapies were well tolerated. CONCLUSIONS: In type 2 diabetic patients, miglitol in combination with metformin gives greater glycemic improvement than metformin monotherapy.

Effects of continuous subcutaneous insulin infusion versus multiple injections on insulin receptors in insulin-dependent diabetics.

We compared continuous subcutaneous insulin infusion (CSII) versus multiple injections (MI) in the treatment of insulin-dependent diabetes mellitus (IDDM) to assess the effect of glucose control on monocyte insulin receptors. Each IDDM patient (n = 8) was treated for 2 mo by MI (HS Ultralente and AC boluses of regular insulin) and for 2 mo by CSII in a randomized fashion. Prestudy preprandial/postprandial blood glucose levels were 199 +/- 33/261 +/- 28 mg/dl and improved to 124 +/- 12/156 +/- 13 mg/dl during MI and to 115 +/- 11/151 +/- 11 mg/dl during CSII. Glycosylated hemoglobin before the study was 10.1 +/- 0.5% and decreased to 8.8 +/- 0.4 and 8.3 +/- 0.3% during MI and CSII, respectively. The specific 125I-labeled insulin binding to circulating monocytes in a group of nonobese controls (n = 17) was 4.6 +/- 0.2%. In our poorly controlled diabetics during conventional therapy, the 125I-insulin binding was decreased to 3.7 +/- 0.3 (P less than .025). This was not significantly affected by MI despite good glucose control (4.0 +/- 0.3%). With CSII, however, good glucose control was associated with normalization of 125I-insulin binding to monocytes (4.7 +/- 0.27%). The affinity of the insulin receptors was normal before the study and was not affected by either MI or CSII. In conclusion, these observations demonstrate that in IDDM, intensive therapy by MI and CSII resulted in similar good glucose control, but only CSII resulted in normalization of insulin receptors on circulating monocytes.

Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro).

OBJECTIVE: To evaluate and validate appropriate premeal insulin dose reductions for postprandial exercises of different intensities and durations to minimize the risk of exercise-induced hypoglycemia in type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Eight male type 1 diabetic patients on a basal-bolus insulin regimen of ultralente (UL) as basal insulin and lispro (LP) as premeal insulin were tested in a randomized, crossover fashion during postprandial exercise at 25% VO2max for 60 min, 50% VO2max for 30 and 60 min, and 75% VOmax for 30 min starting 90 min after a standardized mixed breakfast (600 kcal, 75 g carbohydrates). Each subject served as his own control and was rested after a full dose of insulin LP (LP 100%) and/or 50% (LP 50%) and/or 25% (LP 25%) of the current dose. RESULTS: At all intensities, the full premeal insulin dose was associated with an increased risk of hypoglycemia. At 25% VO2max for 60 min, a 50% reduction in the premeal insulin dose resulted in plasma glucose of -0.62 mmol/l compared with baseline at the end of exercise. At 50% VO2max for 30 and 60 min, 50 and 75% reductions of the premeal insulin dose were associated with plasma glucose of -0.39 and +0.49 mmol/l, respectively, at the end of the exercise. At 75% VO2max, a 75% reduction of the premeal insulin dose was required to achieve appropriate postexercise plasma glucose (+0.71 mmol/l). Such reductions in the premeal insulin dose resulted in a 75% decrease in the incidence of exercise-induced hypoglycemia. CONCLUSIONS In well-controlled type 1 diabetic subjects on intensive insulin therapy with the basal-bolus (UL-LP) insulin regimen, risk of hypoglycemia can be minimized during postprandial exercises of different intensities and different durations by appropriate reduction of premeal insulin LP.