Pierre Maheux

Insulin resistance affects the regulation of lipoprotein lipase in the postprandial period and in an adipose tissue-specific manner.

Aims Insulin is a potent stimulator of adipose tissue lipoprotein lipase (LPL). Logically, the postprandial period is therefore a privileged time of the day for the regulation of LPL by insulin in this tissue. It is not clear to what extent a defect such as insulin resistance could affect this regulation and contribute to postprandial, as well as fasting, hypertriglyceridaemia. The aim of the present protocol was to study the relationship between insulin resistance and LPL in adipose tissue and in plasma, in the particular context of the postprandial period.

Effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes.

The sulfonylurea gliclazide and the biguanide metformin have different mechanisms to reduce glycemia. We performed a randomized study to compare these two agents with respect to glycemic control and effects on lipid peroxidation markers in 36 adult patients with type 2 diabetes. Both agents significantly decreased glycosylated hemoglobin ([HbA1c] P < .05), fructosamine (P < .05), and the glucose-excursion curve during the oral glucose tolerance test ([OGTT] P < .01). With regard to the insulin curve during this test, no significant change was observed with metformin and a significant increase was measured with gliclazide (P < .05). Considering the small number of events, no significant difference was detected in the number of hypoglycemic episodes between the two agents. More upper-gastrointestinal (GI) symptoms were observed with metformin compared with gliclazide (P < .05). Even with no change in the standard lipid profile, both agents increased serum vitamin E (P < .01 for gliclazide and P < .05 for metformin) and decreased the level of lipid peroxidation markers in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles (P < .05). Despite different mechanisms of action, gliclazide and metformin demonstrated comparable levels of efficacy and complementary effects on lipid peroxidation markers.

Acarbose in the treatment of elderly patients with type 2 diabetes.

AIMS To study the effect of acarbose, an alpha-glucosidase inhibitor, on glycemic control in elderly patients with type 2 diabetes. METHODS Elderly patients with type 2 diabetes treated with diet alone were randomly treated in a double-blind fashion with placebo (n=99) or acarbose (n=93) for 12 months. RESULTS After 12 months of therapy, there was a statistically significant difference in the change in glycated haemoglobin (HbA(1c)) (-0.6%) in the acarbose group versus placebo, as well as in the incremental post-prandial glucose values (-2.1 mmol h/l) and mean fasting plasma glucose (-0.7 mmol/l). Although there was no effect of acarbose on insulin release, there was a clear effect of acarbose to decrease relative insulin resistance (-0.8) (HOMA method). In addition, acarbose was generally well tolerated and safe in the elderly; most discontinuations were due to gastrointestinal side effects such as flatulence and diarrhea. There were no cases of hypoglycemia reported, and no clinically relevant changes in laboratory abnormalities or vital signs during the study. CONCLUSIONS Acarbose improves the glycemic profile and insulin sensitivity in elderly patients with type 2 diabetes who are inadequately controlled on diet alone.

Efficacy of intensive multitherapy for patients with type 2 diabetes mellitus: a randomized controlled trial

Background: National guidelines for managing diabetes set standards for care. We sought to determine whether a 1-year intensive multitherapy program resulted in greater goal attainment than usual care among patients with poorly controlled type 2 diabetes mellitus. Methods: We identified patients with poorly controlled type 2 diabetes receiving outpatient care in the community or at our hospital. Patients 30–70 years of age with a hemoglobin A1c concentration of 8% or greater were randomly assigned to receive intensive multitherapy (n = 36) or usual care (n = 36). Results: The average hemoglobin A1c concentration at entry was 9.1% (standard deviation [SD] 1%) in the intensive therapy group and 9.3% (SD 1%) in the usual therapy group. By 12 months, a higher proportion of patients in the intensive therapy group than in the control group had achieved Canadian Diabetes Association (CDA) goals for hemoglobin A1c concentrations (goal ≤ 7.0%: 35% v. 8%), diastolic blood pressure (goal < 80 mm Hg: 64% v. 37%), low-density lipoprotein cholesterol (LDL-C) levels (goal < 2.5 mmol/L: 53% v. 20%) and triglyceride levels (goal < 1.5 mmol/L: 44% v. 14%). There were no significant differences between the 2 groups in attaining the targets for fasting plasma glucose levels, systolic blood pressure or total cholesterol:high-density lipoprotein cholesterol ratio. None of the patients reached all CDA treatment goals. By 18 months, differences in goal attainment were no longer evident between the 2 groups, except for LDL-C levels. Quality of life, as measured by a specific questionnaire, increased in both groups, with a greater increase in the intensive therapy group (13% [SD 10%] v. 6% [SD 13%], p < 0.003). Interpretation: Intensive multitherapy for patients with poorly controlled type 2 diabetes is successful in helping patients meet most of the goals set by a national diabetes association. However, 6 months after intensive therapy stopped and patients returned to usual care, the benefits had vanished.

Increased Extravasation of Macromolecules in Skeletal Muscles of the Zucker Rat Model

Objective: Assess whether changes in permeability of the muscle regional microcirculation occur in the obese Zucker rat model.

Reduction of capillary permeability in the fructose-induced hypertensive rat

Impaired insulin transcapillary transport and the subsequent decrease in insulin delivery to target organs have been suggested to play a role in insulin resistance. These defects were studied in fructose-fed rats, an animal model with insulin resistance. For this study, male Sprague-Dawley rats were fed with either a 60% fructose enriched (F) or a standard chow diet (N) for a total of 2, 4, or 8 weeks. Capillary permeability to albumin was assessed at the end of each dietary period by quantifying the extravasation of albumin-bound Evans blue (EB) dye in different organs. Unanesthetized animals were injected with Evans blue dye (20 mg/kg) in the caudal vein 10 min before being killed and EB dye was extracted by formamide from selected organs collected after exsanguination. As expected, rats had an increase in blood pressure upon feeding with fructose at 4 and 8 weeks (F, 149 +/- 3 mm Hg; N, 139 +/- 3 mm Hg; P < .05). Using this technique, we showed a 56% and a 51% reduction in capillary permeability in skeletal muscles at 4 and 8 weeks of fructose feeding, respectively (4 weeks: N, 44.5 +/- 5.0 microg/g of dry tissue; F, 19.8 +/- 4.2 microg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 +/- 3.7 microg/g of dry tissue; F, 11.3 +/- 4.0 microg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 +/- 8.8 microg/g of dry tissue; F, 53.0 +/- 5.1 microg/g of dry tissue; P < .02) and skin (N, 36.0 +/- 5.3 microg of dry tissue; F, 15.0 +/- 2.3 microg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 +/- 4.3 microg/g of dry tissue; F, 80.9 +/- 3.2 microg/g of dry tissue; P < .01). In conclusion, fructose feeding is accompanied by a significant and selective reduction of Evans blue leakage primarily in skeletal muscle and liver, and transiently in the skin and aorta, consistent with a role for decreased tissue insulin delivery in insulin resistance.

Induction of cholesteryl ester transfer protein in adipose tissue and plasma of the fructose-fed hamster

Cholesteryl ester transfer protein (CETP) plays a pivotal role in the reverse transport of cholesterol and in the remodeling of circulating lipoproteins. While plasma and adipose tissue levels of CETP are affected by a variety of metabolic conditions, the extent of the effects of dietary factors, other than high cholesterol feeding, are not well understood. To further explore this paradigm, male Golden Syrian hamsters were fed for 4 weeks with a 60%-enriched fructose diet (F) and were compared to a matched group of animals fed with a normal chow diet (N). After feeding for 4 weeks, plasma insulin concentrations were lower in animals fed fructose than in control animals (F: 3.3+/-0.8 vs N: 7.4+/-1.9 ng/mL; p<0.03), but there was no significant difference in plasma glucose concentrations between the two groups (F: 138+/-7 vs N: 148+/-10 mg/dL; p>0.05). Fructose-fed animals showed significant increases in plasma triglyceride (F: 269+/-22 vs N: 165+/-22 mg/dL; p<0.01) and plasma cholesterol (F: 150+/-10 vs N: 113+/-6 mg/dL; p<0.02) concentrations compared with control animals. Total CETP activity and immunoreactive mass were higher in the plasma of fructose-fed animals that in that of controls (F: 1036+/-70 vs N: 826+/-43 pmol/h/mL, p<0.04 and F: 24.5+/-3.1 vs N: 37.5+/-4.3 AU, p<0.02, respectively). Adipose tissue CETP mRNA levels, assessed by the very sensitive ribonuclease protection assay, were 53% higher in fructose-fed animals than in controls (F: 14.1+/-2.0 vs N: 9.2+/-1.0 AU over a rRNA control; p<0.04). Adipose tissue CETP activity and immunoreactive mass also showed a statistically significant increase in the fructose-fed hamsters compared with those fed a normal diet (p<0.04). In conclusion, fructose feeding in Syrian hamsters induces a mixed dyslipidemia. These metabolic changes are accompanied by a significant increase in CETP levels, both in plasma and in adipose tissue. This phenomenon suggests that the increase in the expression of adipose tissue CETP may be caused either by the ambient hypercholesterolemia resulting from fructose feeding or by an attenuation of a possible inhibitory effect of plasma insulin concentrations on the expression of adipose tissue CETP in this feeding paradigm.

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.

Miglitol, an α-glucosidase inhibitor, prevents the metformin-induced fall in serum folate and vitamin B12 in subjects with type 2 diabetes

Abstract Since folate and vitamin B 12 absorption may be increased by colonic bacterial activity, their status may be improved by miglitol, an α-glucosidase inhibitor of potential use in the treatment of diabetes. To test this, subjects with type 2 diabetes were treated for 9 months in a double-blind, randomized controlled fashion with either placebo (n=45), miglitol (n=45), metformin (n=62), or a combination of miglitol and metformin (n=47). Glycated hemoglobin (HbA 1c ), serum and red cell folate and serum vitamin B 12 were measured and 3-day dietary records obtained before and after therapy. Compared to placebo, all 3 active treatments significantly reduced HbA 1c , metformin to a greater extent than miglitol and the combination to a greater extent than metformin. Dietary folate intake did not change on any treatment. Serum folate and vitamin B 12 , respectively, did not change on placebo, but fell by 14% and 15% on metformin and rose by 12% and 23% on miglitol. The changes in folate and vitamin B 12 concentrations on metformin were significantly different from those on miglitol. On combination therapy, both folate and vitamin B 12 tended to rise, but the difference from metformin was only significant for folate. These data support the hypothesis that increased carbohydrate delivery to the colon increases intestinal biosynthesis of folate. The combination of miglitol with metformin may prevent the metformin-induced fall in serum folate and vitamin B 12 .

The TNF-α-238G > A single-nucleotide polymorphism protects against memory decline in older adults with type 2 diabetes

Inflammatory markers predict memory dysfunction in elderly patients, but their contribution to memory deficits in adults with Type 2 diabetes mellitus (T2DM) is less well understood. The present study determined whether specific single-nucleotide polymorphisms in the promoter region of tumor necrosis factor-alpha (TNF-alpha) predict verbal memory in older patients with T2DM. Immediate and delayed verbal memory were assessed using word list and paragraph recall tests in a cohort of subjects with T2DM during 2 sessions, separated by 48 weeks. The presence of the TNF-alpha-238A allele, which has been shown to decrease gene expression, consistently predicted better baseline performance and protected against memory decline over a period of 48 weeks. Therefore, inflammatory mediators may be important modulators of memory function in individuals with T2DM.