Hepatic fat content is a determinant of postprandial triglyceride levels in type 2 diabetes mellitus patients with normal fasting triglyceride

Postprandial hypertriglyceridemia is common in type 2 diabetes mellitus (T2D). Significant numbers of T2D patients who have normal fasting triglyceride (TG) have postprandial hypertriglyceridemia. The role of regional adipose tissue and adiponectin on postprandial TG responses in this group of T2D patients is unclear. This study aimed to examine the contribution of regional adipose tissue and adiponectin to the variation of postprandial TG responses in T2D patients who have normal fasting TG levels. Thirty-one Thai T2D patients who had fasting TG<1.7 mmol/L were studied. All were treated with diet control or sulphonylurea and/or metformin. None was treated with lipid-lowering agents. Mixed-meal test was performed after overnight fast. Plasma glucose, insulin, and TG were measured before and 1, 2, 3, and 4 hours after the test. Adiponectin was measured in fasting state. Visceral as well as superficial and deep subcutaneous abdominal adipose tissues were determined by magnetic resonance imaging, and hepatic fat content (HFC) was determined by magnetic resonance spectroscopy. Univariate and multivariate regression analyses of postprandial TG and regional adipose tissue and metabolic parameters were performed. The TG levels before and 1, 2, 3, and 4 hours after the mixed meal were 1.32+/-0.40 (SD), 1.40+/-0.41, 1.59+/-0.40, 1.77+/-0.57, and 1.80+/-0.66 mmol/L, respectively (P<.0001). The area under the curve (AUC) of postprandial TG was positively and significantly correlated with fasting TG (r=0.84, P<.0001) and log.HFC (r=0.456, P=.033) and was inclined to be correlated with log.deep subcutaneous adipose tissue (r=0.38, P=.05) and sex (r=0.326, P=.073). The AUC of postprandial TG was not correlated with age, body mass index, waist circumference, log.superficial subcutaneous adipose tissue, log.visceral adipose tissue, hemoglobin A1c, fasting glucose, AUC.glucose, log.fasting insulin, log.AUC.insulin, log.homeostasis model assessment%B, log.homeostasis model assessment of insulin resistance, and adiponectin. Only fasting TG (beta=.815, P<.0001) and log.HFC (beta=.249, P=.035) predicted AUC of postprandial TG in regression model (adjusted R2=0.84, P<.0001). In conclusion, in T2D patients with normal fasting TG, the increase of postprandial TG levels is directly determined by fasting TG level and the amount of hepatic fat.     

Insulin lispro (Lys(B28), Pro(B29) in the treatment of diabetes during the fasting month of Ramadan. Ramadan Study Group.

AIMS: To compare insulin lispro with soluble human insulin in patients with Type 2 diabetes mellitus fasting during Ramadan, with respect to the rate of hypoglycaemic episodes and postprandial blood glucose values after the main meal after sunset. METHODS: The insulins were compared in an open-label, randomized, cross-over study of 70 outpatients. Hypoglycaemic episodes were recorded by the patients in a self-monitoring diary. Fasting, 1-h and 2-h postprandial blood glucose values were recorded by the patient on three consecutive days at the end of each treatment period. RESULTS: The fasting blood glucose values before sunrise (P>0.4) and after sunset (P>0.6) were similar and did not differ significantly between both treatment groups. The rise in blood glucose after the main meal after sunset was 3.0+/-0.4 mmol/l after 1 h in the insulin lispro treatment group compared to 4.3+/-0.4 mmol/l in the soluble insulin treatment group (P<0.01), and 2.6+/-0.4 mmol/l after 2h with insulin lispro compared to 4.0+/-0.5 mmol/l with soluble insulin (P<0.008). Mean hypoglycaemic episodes per patient over 14 days were 1.3+/-0.1 vs. 2.6+/-0.2, P<0.002, respectively, for insulin lispro and soluble insulin. Most hypoglycaemic episodes occurred during the time period from 6 h after the before sunrise meal until breaking the fast after sunset. CONCLUSIONS: The significantly lower rate of hypoglycaemic episodes combined with better control of postprandial blood glucose suggest insulin lispro may be more suitable prandial insulin for patients treated with Type 2 diabetes who fast during Ramadan.     

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.

AIM: To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. METHODS: This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. RESULTS: Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). CONCLUSIONS: In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.     

Postprandial hypertriglyceridaemia in treated type 2 diabetic subjects --the role of dietary components

Postprandial hyperlipidaemia is a risk factor for cardiovascular diseases (CVD). This study was done (a) to evaluate whether postprandial hypertriglyceridaemia was common in Indian type 2 diabetic patients on treatment and (b) to see whether the high carbohydrate content of the diet was a cause of the lipid abnormality. Two hundred type 2 diabetic subjects (M:F, 137:63; mean age 51.6+/-10.2 years, mean BMI 25.5+/-3.1 kg/m(2)) with diabetes duration of 7.6+/-5.6 years were studied. Fasting and 2 h post prandial responses of plasma glucose and triglycerides (TG) were measured using a breakfast meal, usually consumed by the patient with the intake of usual hypoglycaemic drugs. Patients with a post prandial TG value greater than 15% of the corresponding fasting TG value were designated as group 2 and the remaining subjects as group 1. Dietary composition of the breakfast were calculated. Among the 200 subjects, 52 (26%) had post prandial TG higher than the fasting values. This was seen in patients who were consuming lower percentage of carbohydrates and higher percentage of fats than prescribed. Therefore the postprandial rise in TG was probably due to the high fat content of the diet and due to a lower insulin sensitivity. This study highlights the facts that postprandial hypertriglyceridaemia is seen only in a small proportion of the treated patients and the high carbohydrate diet does not produce hypertriglyceridaemia, either in the fasting or post prandial state. The minority who show an increased TG value at 2 h have been taking lower carbohydrate with higher fat content in the meal. This could have produced a lower insulin sensitivity in these patients.     

Acarbose lowers serum triglyceride and postprandial chylomicron levels in type 2 diabetes

AIM: This study was designed to examine the therapeutic effect of acarbose on serum triglyceride (TG), free fatty acid (FFA), very low-density lipoprotein (VLDL) and chylomicron (CM) in the meal tolerance test (MTT) before and after acarbose treatment in type 2 diabetes mellitus (DM2). METHODS: Effects of acarbose on postprandial lipid metabolism were examined in DM2 patients. The subjects with normotriglyceridaemia (TG > or = 1.7 mmol/l, n = 60) were divided to three groups (A, B and C), and DM2 patients with hypertriglyceridaemia (TG > 1.7 mmol/l, n = 20) were designated group D. Group A was a control, and group B was designed to examine the one-dose effect of acarbose (100 mg) on lipid levels in MTT using the balanced food of 400 kcal. In groups C and D, acarbose 300 mg/day was administered for 8 weeks, and MTT with the one-dose acarbose administration was performed. We determined the levels of fasting and postprandial levels of glucose, insulin, FFA and TG-rich lipoproteins such as CM and VLDL. RESULTS: Acarbose treatment lowered plasma glucose levels and insulin secretion. In comparison among study groups A, B and C, acarbose significantly lowered serum TG levels in postprandial state. In group D, after the 8-week acarbose administration, fasting or postprandial FFA, TG and VLDL levels were also lowered. Interestingly, postprandial increase in CM was suppressed by acarbose administration in group B, C or D. CONCLUSIONS: Acarbose lowers postprandial TG and CM levels in DM2 with either normotriglyceridaemia or hypertriglyceridaemia. Improvement of insulin resistance with acarbose may also reduce fasting TG levels in DM2 with hypertriglyceridaemia. Acarbose is a beneficial therapeutic agent to reduce TG levels in DM2 patients, thereby leading to suppression of cardiovascular events.     

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Postprandial plasma glucose: a good index of glycemic control in type 2 diabetic patients having near-normal fasting glucose levels

To investigate the effect of postprandial plasma glucose (PG) concentrations on HbA1c levels in type 2 diabetic patients, we evaluated the relationship between HbA1c levels and postprandial PG concentrations after a meal tolerance test in 35 type 2 diabetic patients who had fasting PG concentrations persistently < 7.8 mmol/l and stable HbA1c levels. Two-hour postprandial PG concentrations were found to be more strongly correlated (r = 0.51) with HbA1c levels than 1-h postprandial PG (r = 0.35) and fasting PG (r = 0.46) concentrations. Patients whose HbA1c levels were high (HbA1c > or = 7%) had significantly higher 2-h postprandial PG concentrations and areas under the glucose curve than those whose HbA1c levels were lower (8.12+/-1.10 (SD) vs 6.70+/-2.22 mmol l(-1), P = 0.004 and 17.43+/-1.92 vs 15.58+/-3.26 mmol h(-1) l(-1), P = 0.02, respectively). Although fasting PG concentrations of patients with higher HbA1c levels were slightly higher, they did not differ significantly from those with lower HbA1c levels (6.21+/-0.89 vs 5.73+/-0.68 mmol l(-1)). Age, duration of diabetes, body mass index, serum C-peptide, both fasting and postprandial, did not differ between these two groups. This study suggests that postprandial hyperglycemia, particularly 2-h postprandial PG concentrations, is associated with high HbA1c levels in type 2 diabetic patients whose fasting PG levels were within normal or near-normal levels.     

Insulin sensitivity predicts glycemia after a protein load

Protein ingestion results in small but distinct changes in plasma glucose and insulin. We hypothesized that the glycemic and/or insulin response to protein might be related to the degree of insulin sensitivity. Our aim was to determine the relationships between insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp) and postprandial glucose, insulin, C-peptide, and glucagon responses to a 75-g protein meal and a 75-g glucose load. Sixteen lean healthy Caucasian subjects (mean +/- SD age, 25 +/- 6 years; body mass index [BMI], 23.1 +/- 1.7 kg/m2) participated in the study. After the protein meal, the mean plasma glucose declined gradually below fasting levels to a nadir of -0.36 +/- 0.46 mmol/L from 60 to 120 minutes, showing wide intraindividual variation. Insulin sensitivity (M value) was 1.1 to 3.9 mmol/L/m2 min in the subjects and correlated inversely with the plasma glucose response to the protein meal (r = -.58, P = .03), ie, the most insulin-sensitive subjects showed the greatest decline in plasma glucose. In contrast, there was no correlation between insulin sensitivity and the insulin or glucagon response to the protein load, or between the M value and the metabolic responses (glucose, insulin, C-peptide, and glucagon) to the glucose load. Our study suggests that the net effect of insulin and glucagon secretion on postprandial glucose levels after a protein meal might depend on the individual's degree of insulin sensitivity. Gluconeogenesis in the liver may be less susceptible to inhibition by insulin in the more highly resistant subjects, thereby counteracting a decline in plasma glucose.     

No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes

BACKGROUND: To study the acute effect of nateglinide, an insulinotropic agent, on the postprandial triglyceride and lipoprotein responses in subjects at risk for type 2 diabetes. METHODS: Six women and 10 men, with at least one first-degree relative with type 2 diabetes were included (Age: 48 +/- 7 years, BMI: 27.5 +/- 2.8 kg m(-2), P-triglycerides: 1.3 +/- 0.4 mmol L(-1), P-cholesterol: 5.4 +/- 0.6 mmol L(-1), B-glucose: 4.6 +/- 0.3 mmol L(-1)). They each had two 8-h meal tolerance tests with either nateglinide or placebo given 10 min prior to the meals in randomized order. Lipoprotein fractions were separated by density gradient ultracentrifugation. First-phase insulin secretion was assessed by an intravenous glucose tolerance test (300 mg kg(-1) body weight) and insulin sensitivity by a hyperinsulinaemic euglycaemic clamp (40 mU m(-2) min(-1)). RESULTS: The 1-h insulin levels during the meal tolerance test were significantly higher with nateglinide (577 +/- 81 vs 376 +/- 58 pmol L(-1), p < 0.001), as well as the response during the first two hours (IAUC: 41 243 +/- 5844 vs 29 956 +/- 4662 pmol L(-1) min, p < 0.01). Accordingly, nateglinide lowered the 8-h postprandial glucose response by around 60% compared to placebo (p < 0.001). In contrast, no significant lowering was seen in the excursion of postprandial triglycerides in total plasma or lipoprotein fractions. Consistently, the concentration of exogenous (apoB-48) and endogenous (apoB-100) lipoproteins was not reduced by nateglinide. CONCLUSIONS: Acute administration of nateglinide reduces, as expected, the postprandial glucose concentration, but no reduction in triglyceride or lipoprotein responses are seen in subjects at risk for type 2 diabetes.     

Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus

This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).     

Glycemic responses of oat bran products in type 2 diabetic patients

BACKGROUND AND AIM: Cereal products with low postprandial glycemic response are encouraged in the management of hyperglycemia. In this study, we determined the postprandial glycemic response of two different oat bran products in patients with type 2 diabetes. In addition, we investigated the effects of oat bran flour on postprandial glucose response following an oral glucose load. METHODS AND RESULTS: A randomized, controlled, repeated measures design with two test series was used. Twelve type 2 diabetic patients participated in five 2-h meal glucose tolerance tests on separate occasions. Volunteers were given in random order oat bran flour, oat bran crisp and glucose load providing 12.5 g glycemic carbohydrate (series 1), 25 g glucose load alone and 25 g glucose load with 30 g oat bran flour (series 2). Finger-prick capillary blood analysis was carried out fasting and then 15, 30, 45, 60, 90 and 120 min after the start of the meal. The oat bran flour had a lower 0-120 min area under the glucose response curve (AUC) (47+/-45 mmol min/L) than the glucose load (118+/-40 mmol min/L) (p<0.002), but there was no difference between the oat bran crisp (93+/-41 mmol min/L) and the glucose load in this respect. The oat bran flour decreased the glucose excursion from baseline by 1.6 mmol/l (2.4, 0.8) (mean (95% CI)) and 1.5 mmol/l (2.0, 1.1) at 30 and 45 min after the glucose load, respectively. CONCLUSIONS: Oat bran flour high in beta-glucan had a low glycemic response and acted as an active ingredient decreasing postprandial glycemic response of an oral glucose load in subjects with type 2 diabetes.     

Men at increased risk of coronary heart disease are not different from age- and weight-matched healthy controls in their postprandial triglyceride, nonesterified fatty acid, or incretin responses to sucrose

Short-term studies suggest that extreme sucrose consumption has a detrimental effect on triglycerides (TG) in hypertriglyceridemic people. There is currently no consensus on the short-term inclusion of a moderate intake of sucrose in middle-aged men at increased risk of coronary heart disease (CHD). It is also unknown whether gut hormones that are released in response to carbohydrate ingestion modulate any of the effects of sucrose. The aim of this study was to further elucidate whether men at increased risk of CHD have an exaggerated response to sucrose compared with age- and weight-matched controls over an acute postprandial period. Twenty middle-aged men were recruited and separated into control (total cholesterol < 5.5 mmol/L) and increased risk of CHD (> 5.5 mmol/L) groups. We measured postprandial TG, nonesterified fatty acids (NEFA), insulin, glucose, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations in response to a meal containing 75 g glucose or 75 g sucrose with a moderate fat load. The increased risk group had significantly higher Framingham risk assessment (12% v 4%), TG (2.4 +/- 1.5 v 1.1 +/- 0.4 mmol/L), low-density lipoprotein-cholesterol (LDL-C) (4.4 +/- 0.5 v 2.7 +/- 0.4 mmol/L), and lower high-density lipoprotein-cholesterol (HDL-C) (1.2 +/- 0.2 v 1.5 +/- 0.2 mmol/L) (P <.05 for all). There was no significant difference in the incremental area under the curve (IAUC, 0 to 360 minutes) for TG, NEFA, glucose, GLP-1, or GIP in response to glucose or sucrose within or between the groups. Absolute total area under the curve (not IAUC) for TG was significantly higher in the increased risk group for both glucose and sucrose, respectively (P =.01). A total of 75 g of sucrose given as part of a single meal appears to make little difference in the postprandial TG and NEFA response in men with or without risk of CHD compared with glucose. Although long-term data is needed, this begs the question whether a moderate intake of sucrose has been overemphasized as a detrimental dietary message in middle-aged men.     

Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes

BACKGROUND: It has been shown that insulin resistance syndrome, including glucose intolerance, dyslipidemia, and hypertension, is frequently associated with coronary artery disease (CAD). However, their relative contributions and predictive power in the development of CAD are still unclear, particularly in persons without diabetes. METHOD: We examined these risk factors between 96 patients without diabetes but with angiographically documented CAD and 96 age-, sex-, and body mass index-matched healthy control subjects. Fasting plasma lipoprotein, glucose, and insulin concentrations in response to a 75-g oral glucose tolerance test were determined, and insulin sensitivity was measured by the insulin suppression test. RESULTS: Patients with CAD had significantly higher values of fasting glucose, glucose and insulin responses to oral glucose tolerance test, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride and decreased high-density lipoprotein (HDL) cholesterol concentrations compared with those of healthy people (P < 0.02-0.001). Although the steady-state plasma insulin values were similar in both groups, the steady-state plasma glucose (SSPG) concentrations were significantly higher in patients with CAD (12.2+/-0.4 versus 8.1+/-0.4 mmol/L, P < 0.001) compared with healthy subjects. When HDL < 0.9 mmol/L, LDL cholesterol > or = 4.1 mmol/L, triglyceride > or = 2.3 mmol/L, SSPG > or = 10.5 mmol/L, and presence of hypertension were defined as separate risk factors for CAD, significantly higher odds-ratio values were observed in patients with CAD compared with healthy people. From logistic multiple regression analysis, SSPG was the strongest risk, followed by lowered HDL cholesterol, elevated triglyceride and LDL cholesterol, and hypertension, to predict CAD. These 5 factors accounted for 36% of total risk for development of CAD in persons without diabetes. CONCLUSIONS: Patients without diabetes with CAD have abnormal glucose metabolism, hyperinsulinemia, and insulin resistance. Degree of insulin resistance (SSPG values), plasma lipid values, and history of hypertension together accounted for one third of all risk for CAD, although degree of insulin resistance was the strongest risk factor.     

Determinants of mild fasting hypertriglyceridaemia in non-insulin-dependent diabetes

Factors contributing to fasting hypertriglyceridaemia were studied in 20 patients with non-insulin-dependent diabetes--nine with normal triglyceride concentrations [fasting triglyceride 0.94 (range 0.58-1.23) mmol l-1] and eleven with mild fasting hypertriglyceridaemia [fasting triglyceride 2.4 (1.82-4.0) mmol l-1]. The patients with hypertriglyceridaemia were more obese [body mass index 29.0 (24.6-33.8) vs. 25.7 (21.9-30.1) kg m-2, P less than 0.05] and demonstrated impaired glucose disposal in response to exogenous insulin at isoglycaemia [insulin sensitivity index, SIp 0.7 (0.27-2.5) vs. 2.4 (0.62-5.1) ml m-2 min per mU l-1, P less than 0.001]. Basal non-esterified fatty acid (NEFA) and glycerol concentrations were higher and were suppressed to a lesser extent during isoglycaemic hyperinsulinaemia. Fasting glucose and apolipoprotein B concentrations were higher in the hypertriglyceridaemic patients, but lipoprotein lipase activities were similar in the two groups. When the effect of obesity was removed (by weight-matching six normotriglyceridaemic with seven hypertriglyceridaemic patients) basal NEFA and glycerol concentrations and the suppression of NEFA in response to insulin remained significantly different between the two groups. We propose that defects in both the glucoregulatory and antilipolytic actions of insulin contribute to mild fasting hypertriglyceridaemia in NIDDM, and that these defects cannot be attributed solely to obesity. These disorders of insulin action may also have important implications for the postprandial metabolism of triglyceride-rich lipoproteins and hence atherogenesis.     

Insulin and C-peptide responses to 75 g oral glucose load in the healthy man

Plasma insulin and C-peptide levels in the fasting state and after a 2-h 75 g oral glucose tolerance test (OGTT) in a large number of healthy subjects are reported. 247 volunteers (134 males, 113 females), aged 13-69 years, who had a negative history of diabetes, no history of significant disease, normal physical examination, normal body weight, normal glucose tolerance, normal blood tests, and who were taking no drugs were studied. Results, mean +/- SEM (range): fasting glucose concentration = 4.64 +/- 0.03 mmol/l (3.10 - 6.10), 1-h glucose concentration = 5.23 +/- 0.10 mmol/l (2.20 - 9.90), 2-h glucose concentration = 4.11 +/- 0.06 mmol/l (2.00 - 6.80); fasting insulin level = 0.088 +/- 0.002 nmol/l (0.03 - 0.28), 1-h insulin level = 0.45 +/- 0.01 nmol/l (0.06 - 1.63), 2-h insulin level = 0.24 +/- 0.01 nmol/l (0.05 - 1.12); fasting C-peptide concentration = 0.60 +/- 0.01 nmol/l (0.14 - 1.34), 1-h C-peptide concentration = 2.17 +/- 0.05 (0.63 - 8.56), 2-h C-peptide concentration = 1.77 +/- 0.04 nmol/(0.35 - 5.74). Fasting insulin and fasting C-peptide concentrations correlated to post-glucose insulin and C-peptide concentrations, respectively. At each sampling-point insulin concentration correlated to C-peptide concentration. After glucose ingestion, both insulin and C-peptide plasma levels correlated significantly with the corresponding glucose levels. During fasting, C-peptide but no insulin level correlated to glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postprandial lipidemia is normal in non-obese type 2 diabetic patients with relatively preserved insulin secretion

To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with diet only, 12 non-obese patients (8 males, hemoglobin A(1c) [HbA(1c)] 6.80 +/- 0.67%) and 14 controls of similar age, body mass index (BMI), and fasting triglyceride (Tg) were given a test meal (58 g fat, 100,000 IU vitamin A). Fasting low-density lipoprotein (LDL) cholesterol (LDLc), high-density lipoprotein (HDL) cholesterol (HDLc), free fatty acids, and apolipoprotein B (apoB), and fasting and postprandial Tg, retinylpalmitate (RP), LDL size, glucose, and insulin were measured. The homeostasis assessment model (HOMA) index and lipoprotein (Lpl) and hepatic (HL) lipase activities were estimated. Patients showed lower fasting HDLc (1.12 +/- 0.26 v 1.40 +/- 0.28 mmol/L, P =.02) and a trend towards smaller LDL particles, which was significant 4 hours postprandially (25.86 +/- 0.40 v 26.16 +/- 0.30 nm, P =.04). The area under the curve of Tg (AUC-Tg) and RP, and Lpl were similar, but HL was higher in patients (156.63 +/- 23.89 v 118 +/- 43.27 U/L, P =.011). HL correlated inversely with LDL size and directly with the HOMA index. In conclusion, normotriglyceridemic type 2 diabetic patients with insulin resistance but relatively preserved insulin secretion show low fasting HDLc and increased HL, but normal postprandial lipidemia.     

The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers

This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.     

Directly measured insulin resistance and the assessment of clustered cardiovascular risks in hypertension

BACKGROUND: The purpose of the study was to use factor analysis to investigate the contribution of a directly measured insulin sensitivity index, steady-state plasma glucose (SSPG) from insulin suppression test (IST), to a clustering of cardiovascular risk factors in hypertensive subjects. METHODS: A total of 204 nondiabetic hypertensive patients who received IST for SSPG were included for current analysis. Factor analysis was performed to explore the contribution of SSPG as additional information to a clustering of risk factors in these subjects. RESULTS: In factor analysis, SSPG aggregated with metabolic variables in an obesity-hyperinsulinemia domain that included two factors: one with positive loadings for SSPG, 2-h glucose, and Log 2-h insulin; and the other with positive loadings for body mass index, waist circumference, and fasting glucose. Fasting insulin linked the two factors together and explained 38.3% of the total variance. Systolic and diastolic blood pressures were loaded on a blood pressure domain separately. The third domain consisted of two factors: one with positive loadings for Log triglycerides and negative loading for high-density lipoprotein cholesterol; and the other with positive loadings for Log triglycerides and non-high-density lipoprotein cholesterol. The model loaded without SSPG explained a proportion of the total variance (78.5%) similar to that achieved with the model loaded with SSPG (77.1%). CONCLUSIONS: Directly measured insulin sensitivity index SSPG clustered with 2-h glucose and Log 2-h insulin in factor analysis in a cohort consisting entirely of hypertensive subjects. However, the contribution of SSPG as additional information to explain the total variance seems to be insignificant.     

Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.     

Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations.

Elevated plasma insulin and triglyceride (TG) and decreased high-density-lipoprotein (HDL)-cholesterol concentrations have been shown to be risk factors for coronary heart disease (CHD). It has been suggested that these metabolic abnormalities are all secondary to resistance to insulin-stimulated glucose uptake. To examine this in more detail, we divided 18 non-diabetic, moderately overweight, sedentary men aged 25-50 years into three groups on the basis of their steady-state plasma glucose levels (SSPG): a low group, (n = 7; SSPG less than 8.3 mmol l-1), a middle group, (n = 6; SSPG 8.3-11.1 mmol l-1), and a high group (n = 5; SSPG greater than 11.1 mmol l-1). The high group had significantly higher fasting (P less than 0.05) and post-oral glucose challenge (P less than 0.01) insulin concentrations, higher fasting TG (P less than 0.05) and lower fasting HDL-cholesterol (P less than 0.05) concentrations than the other two groups. However, there were no statistically significant differences between the groups with regard to body mass index, waist-to-hip ratio or physical endurance capacity as determined by maximal oxygen consumption during a treadmill test. The data suggest that insulin resistance has an effect on the modulation of plasma insulin, TG and HDL-cholesterol concentrations, independent of generalized, abdominal or physical endurance capacity.