Comparison of repaglinide vs. gliclazide in combination with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic agents.

AIMS: This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)]. METHODS: Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l. RESULTS: Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups). CONCLUSIONS: Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.     

Relationship between insulin resistance, insulin secretion and insulin metabolism in simple obesity

The study was designed to evaluate whether the correlation occurring in simple obesity between insulin resistance and peripheral hyperinsulinemia corresponds to a relationship between insulin resistance and insulin overproduction by the pancreas. In addition, the study investigated the relation existing in simple obesity between insulin resistance and insulin metabolism. For these purposes, we measured and correlated: (1) insulin sensitivity, estimated by glucose disappearance rate from plasma after intravenous insulin injection; (2) insulin secretion by the pancreas, estimated by fasting C-peptide levels in peripheral blood; (3) insulin metabolism, estimated by means of C-peptide: insulin molar ratio in peripheral blood. Twenty-five subjects (20 females, five males) aged 21 to 59 years were studied. All were obese and had a normal glucose tolerance. Glucose disappearance rate from plasma after i.v. insulin injection averaged 3.65 +/- 0.42 mg/dl/min (mean +/- s.e.m.). Fasting C-peptide was 0.90 +/- 0.09 nmol/l. Fasting C-peptide: insulin molar ratio averaged 5.94 +/- 0.48. Negative correlations were found between glucose disappearance rates after i.v. insulin injection, ie, insulin sensitivity, and fasting concentrations of both insulin (r = -0.806, P less than 0.001) and C-peptide (r = -0.525, P less than 0.01). A positive relationship was found between glucose disappearance rate from plasma after i.v. insulin injection and fasting C-peptide: insulin molar ratio, ie, insulin metabolism (r = 0.707, P less than 0.001). We conclude that in simple obesity insulin overproduction by the pancreas is negatively related to insulin resistance, and insulin resistance and impaired insulin metabolism are strictly related phenomena.     

Influence of gliclazide on glucose-stimulated insulin release in man

Although sulfonylureas (SU) are widely used in the management of patients with non-insulin-dependent diabetes mellitus (NIDDM), there is still debate about their mechanism of action on the pancreatic beta cell. It is unclear whether the effect of SU on insulin release is additive to the effect of glucose, or whether SU act by increasing pancreatic beta-cell sensitivity to glucose (a shift in the dose-response curve of glucose-stimulated insulin release without a change in maximum release). To address this issue, we assessed the influence of the SU gliclazide on glucose-stimulated insulin release in eight healthy male volunteers. Sixty-minute hyperglycemic glucose clamps (blood glucose levels: 8 mmol/L, a submaximal stimulus; and 32 mmol/L, a maximally stimulating concentration) were performed with and without prior oral administration of gliclazide (80 mg) 30 minutes before the glucose clamp. Mean plasma C-peptide increment at 5 minutes (first-phase secretion) obtained during the 8-mmol/L hyperglycemic clamp, was higher on the gliclazide study day than on the control day (1.07 +/- 0.10 v 0.88 +/- 0.10 mmol/L, P less than .05), whereas no difference in plasma C-peptide response was observed during the 32-mmol/L hyperglycemic clamp. Mean plasma C-peptide increment obtained at the end 60 minutes; (second-phase secretion) of the 8-mmol/L hyperglycemic clamps was higher on the gliclazide study day than on the control day (1.36 +/- 0.13 v 1.09 +/- 0.09 mmol/L, P less than .02). No difference was observed in plasma C-peptide response at the end of the 32-mmol/L hyperglycemic glucose clamps.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of short-term glycemic regulation with gliclazide and metformin on postprandial lipemia.

AIM: Exaggerated postprandial lipemia is now accepted as an independent risk factor in atherogenesis in type 2 diabetes mellitus. We investigated if better glycemic control improves fasting and postprandial lipid profile in type 2 diabetic patients in the short-term. METHODS: Thirty-two type 2 diabetic patients were studied before and after desired glycemic regulation with gliclazide and metformin. Basal levels of glucose, total cholesterol, high density lipoprotein, low density lipoprotein, triglyceride, insulin, and C-peptide were evaluated at fasting state. Afterwards, patients were given a standard 400-kcal mixed meal as a breakfast, contaning 35 % fat. At the 2nd and the 4th hours after the breakfast, postprandial glucose, triglyceride, insulin, and C-peptide levels were determined again. RESULTS: Significant decrease was observed in total cholesterol levels after better glycemic regulation (p<0.05). Besides, triglyceride levels decreased significantly from 175.36+/-17.85 mg/dl to 138.73+/-14.93 mg/dl at fasting state (p<0.05), from 197.26+/-20.85 mg/dl to 154.15+/-14.61 mg/dl at the 2nd hour after mixed meal (p<0.05), and from 209.63+/-28.54 mg/dl to 155.63+/-15.68 mg/dl (p<0.05) at the 4th hour after the mixed meal, when better glycemic profile was provided. Area under curve for triglyceride levels decreased significantly with the better glycemic regulation (p<0.01). CONCLUSIONS: Improved glycemic regulation can lower the raised fasting and postprandial triglyceride levels which are important atherosclerotic risk factors in diabetic patients even in short-term. Since this improvement in triglyceride levels comes early, diabetic patients can be evaluated for fasting and postprandial triglyceride levels in the first month of therapy.     

The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation

GH has been proposed as a therapy for patients with HIV-associated fat accumulation, but the pharmacological doses (6 mg/d) used have been associated with impaired fasting glucose and hyperglycemia. In contrast, physiologic doses of GH ( approximately 1 mg/d) in HIV-negative men reduced visceral adiposity and eventually improved insulin sensitivity, despite initially causing insulin resistance. We conducted an open-label study to evaluate the effects of a lower pharmacologic dose of GH (3 mg/d) in eight men with HIV-associated fat accumulation. Oral glucose tolerance, insulin sensitivity, and body composition were measured at baseline, and 1 and 6 months. Six patients completed 1 month and 5, 6 months of GH therapy. IGF-I levels increased 4-fold within 1 month of GH treatment. Over 6 months, GH reduced buffalo hump size and excess visceral adipose tissue. Total body fat decreased (17.9 +/- 10.9 to 13.5 +/- 8.4 kg, P = 0.05), primarily in the trunk region. Lean body mass increased (62.9 +/- 6.4 to 68.3 +/- 9.1 kg, P = 0.03). Insulin-mediated glucose disposal, measured by a euglycemic hyperinsulinemic clamp, declined at month 1 (49.7 +/- 27.5 to 25.6 +/- 6.6 nmol/kg(LBM).min/pmol(INSULIN)/liter, P = 0.04); values improved at month 6 (49.2 +/- 22.6, P = 0.03, compared with month 1) and did not differ significantly from baseline. Similarly, the integrated response to an oral glucose load worsened at month 1 (glucose area under the curve 20.1 +/- 2.3 to 24.6 +/- 3.7 mmol.h/liter, P < 0.01), whereas values improved at month 6 (22.1 +/- 1.5, P = 0.02, compared with month 1) and did not differ significantly from baseline. One patient developed symptomatic hyperglycemia within 2 wk of GH initiation; baseline oral glucose tolerance testing revealed preexisting diabetes despite normal fasting glucose. In conclusion, GH at 3 mg/d resulted in a decrease in total body fat and an increase in lean body mass in this open-label trial. While insulin sensitivity and glucose tolerance initially worsened, they subsequently improved toward baseline. However, the dose of GH used in this trial was supraphysiologic and led to an increase in IGF-I levels up to three times the upper normal range. Because there are known adverse effects of long-term GH excess, the effectiveness of lower doses of GH should be studied. We also recommend a screening oral glucose tolerance test be performed to exclude subjects at risk for GH-induced hyperglycemia.     

Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone

Peripheral insulin levels are determined by beta-cell secretion, insulin sensitivity, and hepatic insulin extraction (HIE). We have previously shown that whereas sulfonylureas reduce insulin extraction, metformin enhances HIE. However, the effects of thiazolidinediones (TZDs) on HIE remain uncertain. Thus, we investigated the potential contribution of hepatic insulin clearance to peripheral insulin levels during rosiglitazone therapy in African Americans with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The study was composed of 12 first-degree relatives with IGT and 17 patients with newly diagnosed type 2 DM. Nineteen healthy relatives with normal glucose tolerance served as controls. Serum glucose, insulin, and C-peptide, and HIE (C-peptide-insulin molar ratios) were measured at t = 0 and 120 minutes during oral glucose tolerance test (OGTT) in all the subjects. The OGTT was performed before and after 3 months of rosiglitazone therapy (4 mg/d x 4 weeks and >8 mg/d x 8 weeks) in patients with IGT and type 2 DM. Insulin resistance index and beta-cell function were calculated in each subject using homeostasis model assessment (HOMA). Rosiglitazone therapy improved but did not normalize the overall glycemic control in the IGT and type 2 DM groups. After rosiglitazone therapy, the mean serum insulin and C-peptide levels at fasting remained unchanged. However, the 2-hour serum glucose and insulin were lower, whereas serum C-peptide was unchanged during 3 months of rosiglitazone treatment. Mean insulin resistance index of HOMA was reduced by 30% (4.12 +/- 1.95 vs 6.33 +/- 3.54, P < .05) in the type 2 DM group and by 21% (3.78 +/- 2.45 vs 4.81 +/- 3.49, P = NS) in the IGT group. Mean HIE values were significantly lower (70%) in the type 2 DM and IGT groups when compared with the normal glucose tolerance group. At 3 months, basal HIE was not significantly changed by rosiglitazone therapy in IGT and type 2 DM groups when compared with the baseline (0 month). However, rosiglitazone therapy was associated with increased HIE at 2 hours during OGTT by 40% and 30% in the IGT and type 2 DM groups, respectively, from the baseline (0 month) values. Furthermore, HIE inversely correlated with the insulin resistance index of HOMA (r = -.46, P < .05). We conclude that rosiglitazone therapy improved overall glucose tolerance and enhanced insulin sensitivity in patients with IGT and type 2 DM. Although basal HIE remained unchanged, rosiglitazone therapy increased postglucose challenge HIE in African Americans with IGT and type 2 DM. We speculate that TZDs increase insulin clearance or HIE after oral glucose challenge. This study suggests that in addition to insulin sensitization, rosiglitazone may be involved in insulin metabolism. The significance of the increased insulin clearance by TZD therapy remains uncertain and deserves further investigation in patients with insulin resistance and glucose intolerance.     

Increased insulin sensitivity is associated with reduced insulin and glucagon secretion and increased insulin clearance in man

Insulin secretion is increased in insulin resistance. In this study, we examined whether high insulin sensitivity results in low insulin secretion. Twelve male master athletes [age 25.6 +/- 4.1 (mean +/- SD) yr] and seven male sedentary students (age 25.0 +/- 2.0 yr) underwent a hyperinsulinemic, euglycemic clamp and a glucose-dependent arginine stimulation test. Athletes had high insulin sensitivity [230 +/- 18 vs. 92 +/- 12 (nmol glucose/kg.min)/(pmol insulin/liter), P < 0.001] and low insulin response to arginine (at fasting glucose 135 +/- 22 vs. 394 +/- 60 pmol/liter, P < 0.001), which resulted in unaltered disposition index (32.8 +/- 3.8 vs. 33.5 +/- 3.3 micro mol glucose/kg.min, NS). Also, the C-peptide response to arginine was reduced (at fasting glucose 0.71 +/- 0.09 vs. 0.89 +/- 0.09 nmol/liter, P = 0.034). However, the C-peptide reduction was not as large as the insulin reduction yielding increased disposition index in athletes when calculated from C-peptide data (184 +/- 9 vs. 76 +/- 11 micro mol glucose/kg.min, P < 0.001). This difference is explained by increased insulin clearance among the athletes during the first 5 min after arginine (81.1% +/- 1.8% vs. 53.6% +/- 4.7%, P < 0.001). Also, the glucagon response to arginine was reduced in the athletes (58.8 +/- 6.7 vs. 90.1 +/- 9.9 ng/liter at fasting glucose, P = 0.009). We conclude that high insulin sensitivity results in low islet hormone secretion and increased insulin clearance.     

Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women

OBJECTIVE: Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes. DESIGN: Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol-17 beta with 5 or 10 mg/day dydrogesterone for days 17-28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol-17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9). MEASUREMENTS: Patients underwent measurement of glucose, insulin and C-peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured. RESULTS: In both groups there were significant reductions in fasting glucose, insulin and C-peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P < 0.01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0.05) and hepatic (18% to 31%, P < 0.05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment. CONCLUSIONS: Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause-associated changes in insulin secretion and elimination.     

Mechanisms of acute and chronic hypoglycemic action of gliclazide

An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute IV glucose infusion with [3-³H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t. i. d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA_1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion. Received: 1 June 2000 / Accepted in revised form: 5 December 2000     

Concomitant insulin and sulfonylurea therapy in patients with type II diabetes. Effects on glucoregulation and lipid metabolism

Recent evidence suggests concomitant insulin and sulfonylurea therapy has a theoretical potential in the management of type II diabetes mellitus. In a long-term double-blind, randomized placebo-controlled study of combination therapy, serum glucose, C-peptide, total cholesterol, triglyceride, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were evaluated in insulin-treated patients with poorly controlled, type II diabetes mellitus after addition of either glyburide (n = 10) or placebo (n = 12). Oral glucose tolerance testing was performed at weeks 0, 4, and 16. Clinical characteristics and glycemic control (fasting blood glucose and glycosylated hemoglobin values) were similar at week 0 in both groups. The placebo group had no change in any metabolic parameter throughout the study period. At week 4, glyburide significantly lowered fasting blood glucose and integrated glucose areas (p less than 0.01) compared with values at week 0 (fasting blood glucose 225 +/- 20 versus 286 +/- 27 mg/dl, p less than 0.02). Mean fasting, stimulated, and integrated C-peptide levels were significantly higher (p less than 0.02) at week 4 versus week 0. At week 16, mean fasting blood glucose values remained significantly lower compared with baseline values (252 +/- 25 versus 286 +/- 27 mg/dl, p less than 0.05). Glycosylated hemoglobin levels decreased significantly (p less than 0.05) at weeks 4 to 16 compared with the baseline values. Although glucose responses and integrated areas were no different after oral glucose tolerance testing, fasting and stimulated C-peptide levels were significantly higher (p less than 0.05) at week 16 versus week 0. Lipid and lipoprotein levels remained unchanged. In summary, combination therapy consisting of glyburide and insulin moderately improved glucose control in type II diabetes mellitus at the end of four weeks. Despite significantly lower fasting serum glucose and glycosylated hemoglobin levels after 16 weeks, combination treatment did not normalize glycemic control. Glucose tolerance decreased further after 16 weeks despite persistence of increased endogenous insulin secretion. The role of the combination therapy in the long-term care of patients with type II diabetes mellitus needs further investigation.     

Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus.

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the beta-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of beta-cell sensitivity to glucose after sulfonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of breakfast and bedtime administration of insulin glargine in children and adolescents with Type 1 diabetes

OBJECTIVE: The purpose of this study was to evaluate the effect of administration time of insulin glargine (IG) on glycemic control in children and adolescents with Type 1 diabetes. MATERIALS AND METHODS: A total of 31 children and adolescents (15 F and 16 M) with Type 1 diabetes on intensive therapy (bedtime NPH and premeal insulin aspart) were randomized to receive once-daily IG either at breakfast (breakfast group, n=15) or bedtime (bedtime group, n=16) while continuing insulin aspart premeals for 6 months. Blood glucose levels were measured fasting, preprandially and bedtime. Total daily insulin dose (TDD), body mass index (BMI), glycosylated hemoglobin (HbA(1c)), and frequency of hypoglycemia in the preceding 3 months were assessed at recruitment, third month and sixth month. RESULTS: The dose of IG, TDD, and fasting blood glucose levels were similar in both groups during the study period. The only significant difference in blood glucose levels between breakfast and bedtime groups was found for dinnertime at 6 months (135+/-26mg/dl versus 161+/-33mg/dl, respectively, p=0.035). In the breakfast group, the mean HbA(1c) level was significantly lower than that of baseline at month 6 (9.4+/-2.5% versus 8.0+/-0.9%, respectively, p=0.022), whereas there was no significant change in the bedtime group (9.2+/-2.1% versus 8.9+/-2.2%, respectively). The frequency of hypoglycemia was lower with IG than NPH (2.7+/-2.8/6 months versus 6.4+/-6.7/6 months, respectively, p=0.008). CONCLUSIONS: Once-daily IG at breakfast in children and adolescents with Type 1 diabetes on intensive therapy is more efficacious than bedtime administration to improve metabolic control. Also, the number of hypoglycaemic events decreased with both breakfast and bedtime administrations of IG.     

The effect of gliclazide on plasma insulin, intact and 32/33 split proinsulin in South Asian subjects with Type 2 diabetes mellitus.

AIMS: Previous studies have shown that in Caucasian subjects with Type 2 diabetes mellitus (DM), the sulphonylurea glibenclamide increased insulin secretion without causing an increase in 32/33 split proinsulin secretion. South Asian subjects with Type 2 DM are thought to be more insulin resistant and the effect of sulphonylureas may be different. We therefore investigated the effect of sulphonylurea therapy with gliclazide on beta-cell function in South Asian subjects with newly diagnosed Type 2 DM. METHODS: Glucose, insulin, and intact and 32/33 split proinsulin were measured at diagnostic oral glucose tolerance test (OGTT). After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 6 mmol/l (n = 16) were commenced on gliclazide. RESULTS: At diagnosis, those requiring gliclazide were more hyperglycaemic but there was no difference in weight or fasting insulin concentration than in the diet group. Following diet, in the gliclazide group, weight fell (P < 0.04) with no change in fasting glucose concentration. Fasting intact proinsulin, insulin and 32/33 split proinsulin remained unchanged. After gliclazide therapy weight remained unchanged, but fasting glucose fell (P < 0.003). Fasting insulin and intact proinsulin remained unchanged but 32/33 split proinsulin fell (P < 0.05). Fasting insulin to glucose ratio significantly improved after gliclazide (P < 0.006). CONCLUSIONS: In South Asian subjects treated with gliclazide the reduction in fasting glucose concentrations appears to be due to an improvement in insulin sensitivity as well as in beta-cell function.     

Effects of rosglitazone on plasma adiponectin, insulin sensitivity, and insulin secretion in high-risk African Americans with impaired glucose tolerance test and type 2 diabetes

We examined the metabolic effects of rosiglitazone therapy on glucose control, insulin sensitivity, insulin secretion, and adiponectin in first-degree relatives of African Americans with type 2 diabetes (DM) with impaired glucose tolerance (IGT) and DM for 3 months. The study was comprised of 12 first-degree relatives with IGT, 17 newly diagnosed DM, and 19 healthy relatives with normal glucose tolerance (NGT). Oral glucose tolerance test (OGTT) was performed before and after 3 months of rosiglitazone therapy (4 to 8 mg/d) in patients with IGT and DM. Serum glucose, insulin, C-peptide, and adiponectin levels were measured before and 2 hours during OGTT in the NGT and patients with IGT and DM. Insulin resistance index (HOMA-IR) and beta-cell function (HOMA-%B) were calculated in each subject using homeostasis model assessment (HOMA). Rosglitazone improved the overall glycemic control in the IGT and DM groups. Following rosiglitazone, the beta-cell secretion remained unchanged, while HOMR-IR was reduced in DM by 30% (4.12 +/- 1.95 v 6.33 +/- 3.54, P < .05) and the IGT group (3.78 +/- 2.45 v 4.81 +/- 3.49, P = not significant [NS]). Mean plasma adiponectin levels were significantly (P < .05) lower in the DM (6.74 +/- 1.95 microg/mL) when compared with the NGT group(9.61 +/- 5.09). Rosiglitazone significantly (P < .001) increased adiponectin levels by 2-fold in patients with IGT (22.2 +/- 10.97 microg/mL) and 2.5-fold greater in DM (15.68 +/- 8.23 microg/mL) at 3 months when compared with the 0 month. We conclude that adiponectin could play a significant role (1) in the pathogenesis of IGT and DM and (2) the beneficial metabolic effects of thiazolidinediones (TZDs) in high-risk African American patients.     

Serum C-peptide levels determine glycemic responses in type II diabetic patients treated with combined insulin and sulfonylurea agent

Type II diabetes mellitus is a heterogeneous disease. Selection of either insulin or a sulfonylurea agent in addition to diet is usually made empirically. In patients who fail to respond to either agent alone, the potential benefit of combined insulin and sulfonylurea therapy is unclear. We therefore evaluated nine poorly controlled insulin treated type II diabetic patients after addition of a sulfonylurea agent--glyburide--for four weeks. Glycosylated hemoglobin (HbA1c), serum glucose, and C-peptide responses to oral glucose were evaluated. Based on a reduction of at least 50 mg/dl in the fasting serum glucose (FSG) at the end of the first week of the combination therapy or a FSG of less than 140 mg/dl, two groups were arbitrarily identified: responders (n = 5) and nonresponders (n = 4). Clinical characteristics including mean age, weight, duration of diabetes, daily dose of insulin, and duration of insulin treatment were not statistically different between the two groups. Mean baseline FSG and HbA1c levels were also not statistically different in both groups. An improvement in mean FSG and glucose tolerance occurred in the responders at the end of four weeks of combined therapy (FSG: 291 +/- 25 vs. 189 +/- 6 mg/dl, p less than 0.05; HbA1c 10.76 +/- 0.80 vs. 9.40 +/- 0.21%, p = NS). The nonresponders had no change in glucose tolerance. The mean fasting and stimulated serum C-peptide levels were significantly higher in the responders at week 4 compared with that of the nonresponders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regulation of insulin action and tumor necrosis factor alpha system activity by metformin

BACKGROUND: Tumor necrosis factor alpha has a key role in insulin resistance. We study the effects of metformin on glucose tolerance, insulin resistance, beta cell function, and soluble tumor necrosis factor receptor (sTNFR) levels. METHODS: We performed a double-blind, randomized metformin-placebo study. Twenty-three subjects with impaired glucose tolerance or impaired fasting glucose were studied. Oral glucose tolerance, homeostasis model assessment, and continuous infusion of glucose with model assessment tests were used to evaluate glucose tolerance, insulin sensitivity, and beta cell function, respectively. Soluble tumor necrosis factor receptor levels were measured before and after therapy. Repeated measures analysis of variance was used for statistical analysis. RESULTS: After 12-week treatment, fasting glucose (110.1 +/- 9.9 to 98.9 +/- 15.7 mg/dl, P < .001), fasting insulin (11.6 +/- 5.4 to 8.8 +/- 3.5 mU/L, P = .05), fasting C-peptide (2.5 +/- 0.7 to 1.8 +/- 0.5 ng/mL, P < .05), and achieved C-peptide (5.2 +/- 1.2 to 4.2 +/- 1 ng/mL, P < .05) levels decreased in the metformin group. In addition, there was an improvement in insulin sensitivity (37.4% +/- 15.2% to 50.4% +/- 23.2%, P < .05) with unchanged sTNFR1 (2.0 +/- 0.8 to 2.3 +/- 1.2 microg/L, P = NS) and sTNFR2 (4.8 +/- 1.7 to 4.4 +/- 1.2 microg/L, P = NS) levels. CONCLUSIONS: Metformin is able to reverse insulin resistance and hyperglycemia in high-risk subjects for type 2 diabetes mellitus independently of the effects on tumor necrosis factor alpha system activity.     

Effects of prolonged Acipimox treatment on glucose and lipid metabolism and on in vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus.

The effect of prolonged treatment with Acipimox on in vivo peripheral insulin sensitivity, and on glucose and lipid metabolism, was investigated in patients with NIDDM in a double-blind study. Twelve NIDDM patients were randomized to treatment with either placebo or Acipimox in pharmacological doses (250 mg x 3) for three months. Fasting plasma glucose, insulin, C-peptide and HbA1c concentrations were unaffected after three months of acipimox treatment. However, fasting plasma non-esterified fatty acid (NEFA) concentrations were twofold elevated after Acipimox treatment (1.34 +/- 0.09 vs 0.66 +/- 0.09 mmol/l; p < 0.05). Despite this, repeated acute Acipimox administration after the three months' treatment period enhanced total insulin-stimulated glucose disposal to the same extent as acute Acipimox administration before the treatment period (367 +/- 59 vs 392 +/- 66 mg.m-2.min-1, NS; both p < 0.05 vs placebo glucose disposal) (267 +/- 44 mg.m-2.min-1). In conclusion, insulin resistance or tachyphylaxis towards the effects of Acipimox on insulin stimulated glucose disposal was not induced during prolonged Acipimox treatment. The lack of improvement of blood glucose control in the patients with NIDDM may be due to the demonstrated rebound effect of lipolysis.     

Reduced insulin secretion in normoglycaemic patients with beta-thalassaemia major.

AIMS: To assess insulin sensitivity and secretion in the fasting state in regularly transfused patients with beta-thalassaemia major with normal glucose response during an oral glucose tolerance test and to estimate its possible relation to iron overload. METHODS: We measured fasting glucose, insulin and C-peptide levels in 24 patients with beta-thalassaemia major and 18 control subjects matched for age and body mass index. Insulin sensitivity and insulin release index were calculated according to the homeostasis model assessment (HOMA). Correlations with age, body mass index and serum ferritin were also calculated. RESULTS: Fasting glucose levels in patients were increased compared with control subjects (5.5 +/- 0.12 vs. 4.7 +/- 0.13 mmol/l, mean +/- SEM, P < 0.001). Pancreatic B-cell insulin secretion in the fasting state (estimated by SC(HOMA)) was lower in thalassaemic patients (SC(HOMA) 88.5 +/- 11.11 vs. 184.3 +/- 23.72 in control subjects, P < 0.001). Patients were then divided into those with impaired (IFG) and normal (NFG) fasting glucose. SC(HOMA) was higher in the patients with NFG compared with those with IFG patients (110.6 +/- 17.63 vs. 66.3 +/- 10.88, respectively, P < 0.05) but estimated insulin sensitivity (ISI(HOMA)) was similar. Plasma values of C-peptide correlated positively with ferritin (r = 0.42, P = 0.04) and SC(HOMA) (r = 0.45, P = 0.02) and negatively with ISI(HOMA) (r = -0.43, P = 0.03). CONCLUSIONS: These results support the concept that impaired B-cell function, as reflected by a reduction in the insulin secretion index, is present in beta-thalassaemic patients with normoglycaemia before changes in oral glucose tolerance tests are apparent.     

Insulin sensitivity in newly diagnosed type 1 diabetics after ketoacidosis and after three months of insulin therapy

Tissue sensitivity to insulin (euglycemic insulin clamp technique), hepatic glucose production (3-[3H]glucose infusion) and insulin binding to erythrocyte receptors were studied in 14 newly diagnosed type 1 diabetic patients after the disappearance of ketosis and after 3 months of insulin therapy. The control group consisted of 14 normal subjects. During the two insulin clamp studies, plasma glucose in the diabetic patients was maintained at 5.0 +/- 0.04 (SEM) mmol/liter and 4.9 +/- 0.05 mmol/liter, with corresponding steady state free insulin levels of 90 +/- 4 mU/liter, and 67 +/- 6 mU/liter (P less than 0.02) during the first and second study, respectively. The decline in free insulin levels was due to the development of insulin antibodies during insulin therapy (10 +/- 0.1% vs. 18 +/- 2%, P less than 0.001, serum insulin-binding capacity during the first and second study, respectively). In the normal subjects, steady state plasma glucose and insulin levels were 4.9 +/- 0.1 mmol/liter and 89 +/- 4 mU/liter, respectively. The rate of glucose metabolism (M) in the diabetic patients during the first study (5.13 +/- 0.65 mg/kg X min) was 35% lower than that in the normal subjects (7.94 +/- 0.50 mg/kg X min, P less than 0.005). After 3 months of insulin therapy, M increased by 35% to 6.92 +/- 0.58 mg/kg X min, which was comparable to that in the normal subjects. To compensate for the difference in plasma free insulin levels, we calculated an index for insulin sensitivity by dividing M by the ambient insulin concentration (I). During the 3 months of insulin therapy, M/I rose 2-fold to 11.63 +/- 1.10 mg/kg X min per mU insulin/liter X 100, which was similar to that in normal subjects (9.16 +/- 0.67 mg/kg X min per mU insulin/liter X 100). Five diabetic patients had a partial clinical remission, as determined by normal fasting C-peptide levels. In these patients, insulin sensitivity was 35-50% greater than in those who failed to have a remission (P less than 0.05). Basal hepatic glucose production in the diabetic patients during the first study (2.78 +/- 0.14 mg/kg X min) was 56% higher than in the normal subjects (1.78 +/- 0.04 mg/kg X min, P less than 0.001), and remained unchanged during insulin therapy. During the hyperinsulinemia induced by the clamp, hepatic glucose production was totally suppressed in both the diabetic and control subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)