Modification of therapy from insulin to chlorpropamide decreases HDL cholesterol in patients with non-insulin-dependent diabetes mellitus

In 27 patients with non-insulin-dependent diabetes mellitus, we determined fasting serum glucose, hemoglobin A1, body weight, serum triglycerides, cholesterol, low-density lipoprotein cholesterol (LDL-chol), high-density lipoprotein cholesterol (HDL-chol), and very-low-density lipoprotein cholesterol during treatment with insulin and several months after changing treatment to chlorpropamide. In five patients, diabetic control deteriorated to the point where insulin was reinitiated. In the remaining 22 patients, despite a significant decrease in weight (122 +/- 5 vs. 114 +/- 5% ideal body wt; P less than .025) on chlorpropamide, HDL-chol fell from 49 +/- 4 to 40 +/- 4 mg/dl (P less than .01) when therapy was modified from insulin to the sulfonylurea. There was a concomitant increase in LDL-chol:HDL-chol from 3.6 +/- 0.3 to 4.4 +/- 0.5 (P less than .05). In the 5 patients in whom insulin was reinstituted, HDL-chol increased to its previous level on insulin (P less than .05). Changing antidiabetic medication from insulin to sulfonylureas may alter the lipoproteins in a manner that increases cardiovascular risk.     

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).     

No glycemic benefit from guar administration in NIDDM

A randomized crossover study of 5-g guar minitablets against placebo, given three times per day with main meals for 8 wk, was done in 29 non-insulin-dependent diabetes mellitus (NIDDM) patients who had near-normal fasting plasma glucose concentrations on treatment with diet alone, additional sulfonylurea, or ultralente insulin. Guar did not reduce the excessive postprandial glycemic excursion, glycosylated hemoglobin values, basal plasma glucose concentrations, basal or incremental plasma C-peptide values, or body weight. There were few side effects with either guar or placebo therapy. Mean low-density lipoprotein cholesterol levels were significantly reduced (P less than .001) by guar administration (116 +/- 23 vs. 104 +/- 19 mg/dl). Guar additives did not improve the excessive postprandial glycemia found in NIDDM patients in whom near-normal fasting plasma glucose levels had been obtained.     

Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.

The effect of increased Glut4 protein expression in muscle and fat on the whole body glucose metabolism has been evaluated by the euglycemic hyperinsulinemic clamp technique in conscious mice. Fed and fasting plasma glucose concentrations were 172 +/- 7 and 78 +/- 7 mg/dl, respectively, in transgenic mice, and were significantly lower than that of nontransgenic littermates (208 +/- 5 mg/dl in fed; 102 +/- 5 mg/dl in fasting state). Plasma lactate concentrations were higher in transgenic mice, (6.5 +/- 0.7 mM in the fed and 5.8 +/- 1.0 mM in fasting state) compared with that of non-transgenic littermates (4.7 +/- 0.3 mM in the fed and 4.2 +/- 0.5 mM in fasting state). In the fed state, the rate of whole body glucose disposal was 70% higher in transgenic mice in the basal state, 81 and 54% higher during submaximal and maximal insulin stimulation. In the fasting state, insulin-stimulated whole body glucose disposal was also higher in the transgenic mice. Hepatic glucose production after an overnight fast was 24.8 +/- 0.7 mg/kg per min in transgenic mice, and 25.4 +/- 2.7 mg/kg per min in nontransgenic mice. Our data demonstrate that overexpression of Glut4 protein in muscle increases basal as well as insulin-stimulated whole body glucose disposal. These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus.     

Effects of alpha-glucosidase inhibition on meal glucose tolerance and timing of insulin administration in patients with type I diabetes mellitus

OBJECTIVE: Miglitol, an alpha-glucosidase inhibitor, delays absorption of carbohydrates. This study was undertaken to determine the potential of this agent as an adjunct to insulin in the treatment of diabetes. RESEARCH DESIGN AND METHODS: Twelve nonobese patients with insulin-dependent (type I) diabetes mellitus were randomly selected from the outpatient diabetes clinic. The patients were made euglycemic with the Biostator, and postprandial hyperglycemia was determined under the following conditions: protocol 1, subcutaneous injection of insulin (13 +/- 1 U) given 60 min before the meal, with insulin dosages determined by the Biostator; protocols 2 and 3 same as protocol 1 but with insulin given at the time of meal ingestion; protocols 4 and 5 same as protocol 1 but with insulin given 30 min before the meal. Miglitol (100 mg) was administered in protocols 2 and 4 and placebo in protocols 3 and 5. RESULTS: When insulin was given 30 min before the meal with miglitol (protocol 4) or placebo (protocol 5), plasma glucose increased from 4.94 +/- 0.16 to 5.94 +/- 0.55 mM and from 5.11 +/- 0.22 to 8.22 +/- 0.72 mM, respectively (P less than 0.01). When insulin was given at the time of the meal with miglitol (protocol 2) or placebo (protocol 3), plasma glucose increased from 5.44 +/- 0.27 to 7.77 +/- 0.5 mM and from 5.72 +/- 0.22 to 10.83 +/- 0.77 mM, respectively (P less than 0.01). When insulin was given 60 min before the meal (protocol 1), plasma glucose initially decreased from 5.61 +/- 0.38 to 4.33 +/- 0.33 mM and then increased to 6.94 +/- 0.66 mM after the meal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes

OBJECTIVE: To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 58 diet-treated patients with type 2 diabetes (aged 54 +/- 1 years; 34 men and 24 women; BMI 31.5 +/- 0.6 kg/m(2)) were randomly assigned to receive placebo (n=11) or 7.5 mg (n=13), 15 mg (n=12), 30 mg (n=11), or 45 mg (n=11) of pioglitazone per day for 26 weeks. Before and after 26 weeks, subjects underwent a 75-g oral glucose tolerance test (OGTT). RESULTS: Patients treated with 7.5 or 15 mg/day of pioglitazone had no change in fasting plasma glucose (FPG) and fasting plasma insulin (FPI) concentrations or in plasma glucose (PG) and insulin concentrations during the OGTT. Patients treated with 30 and 45 mg/day of pioglitazone, respectively, had significant decreases from placebo in HbA1c (delta=-2.0 and -2.9%), FPG (delta=-66 and -97 mg/dl), and mean PG during OGTT (delta=-84 and -107 mg/dl). Fasting plasma insulin decreased significantly in the 45-mg/day pioglitazone group, but the mean plasma insulin during the OGTT did not change. The insulinogenic index (delta area under the curve [AUC] insulin/deltaAUC glucose) during the OGTT increased significantly in the 30- and 45-mg/day pioglitazone groups (0.13 +/- 0.03 to 0.27 +/- 0.05, P < 0.05). From the OGTT, we previously have derived a composite whole-body insulin sensitivity index (ISI) that correlates well with that measured directly with the insulin clamp technique. Whole-body ISI [ISI=10,000/(square-root (FPG x FPI) x (PG x PI)) where PG and PI equal mean plasma glucose and insulin concentrations during OGTT] increased significantly in patients treated with 30 mg (1.8 +/- 0.3 to 2.5 +/- 0.3, P < 0.05) or 45 mg (1.6 +/- 0.2 to 2.7 +/- 0.6, P < 0.05) per day of pioglitazone. In the basal state, the hepatic ISI [k/(FPG x FPI)[k/(FPG x FPI)], which agrees closely with that measured directly with tritiated glucose, increased in patients treated with 30 mg (0.13 +/- 0.02 to 0.21 +/- 0.03, P < 0.05) and 45 mg (0.11 +/- 0.02 to 0.24 +/- 0.06, P < 0.05) per day of pioglitazone. Significant correlations between the dose of pioglitazone and the changes in HbA1c (r=-0.58), FPG (r=-0.47), mean PG during the OGTT (r=-0.46), insulinogenic index (r=0.34), hepatic ISI (r=0.44), and whole-body ISI (r=0.36) were observed. CONCLUSIONS: Pioglitazone improves glycemic control through the dose-dependent enhancement of beta-cell function and improved whole-body and hepatic insulin sensitivity.     

Efficacy of Ipomoea batatas (Caiapo) on diabetes control in type 2 diabetic subjects treated with diet

OBJECTIVE: To investigate the tolerability, efficacy, and mode of action of Caiapo, an extract of white sweet potatoes, on metabolic control in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 61 type 2 diabetic patients treated by diet were given 4 g Caiapo (n = 30; mean age 55.2 +/- 2.1 years; BMI 28.0 +/- 0.4 kg/m(2)) or placebo (n = 31; mean age 55.6 +/- 1.5 years; BMI 27.6 +/- 0.3 kg/m(2)) once daily for 12 weeks. Each subject underwent a 75-g oral glucose tolerance test (OGTT) at baseline and after 1, 2, and 3 months to assess 2-h glucose levels. Additionally, fasting blood glucose, HbA(1c), total cholesterol, and triglyceride levels were measured. RESULTS: After treatment with Caiapo, HbA(1c) decreased significantly (P < 0.001) from 7.21 +/- 0.15 to 6.68 +/- 0.14%, whereas it remained unchanged (P = 0.23) in subjects given placebo (7.04 +/- 0.17 vs. 7.10 +/- 0.19%). Fasting blood glucose levels decreased (P < 0.001) in the Caiapo group (143.7 +/- 1.9 vs. 128.5 +/- 1.7 mg/dl) and did not change in the placebo group (144.3 +/- 1.9 vs. 138.2 +/- 2.1 mg/dl; P = 0.052). A decrease in body weight was observed in both the placebo group (P = 0.0027) and in the Caiapo group (P < 0.0001), probably due to a better- controlled lifestyle. In the Caiapo group, body weight was related to the improvement in glucose control (r = 0.618; P < 0.0002). Two-hour glucose levels were significantly (P < 0.001) decreased in the Caiapo group (193.3 +/- 10.4 vs. 162.8 +/- 8.2 mg/dl) compared with the placebo group (191.7 +/- 9.2 vs. 181.0 +/- 7.1 mg/dl). Mean cholesterol at the end of the treatment was significantly lower in the Caiapo group (214.6 +/- 11.2 mg/dl) than in the placebo group (248.7 +/- 11.2 mg/dl; P < 0.05). No significant changes in triglyceride levels or blood pressure were observed, and Caiapo was well tolerated without significant adverse effects. CONCLUSIONS: This study confirms the beneficial effects of Caiapo on plasma glucose as well as cholesterol levels in patients with type 2 diabetes. For the first time, the long-term efficacy of Caiapo on glucose control was demonstrated by the observed decrease in HbA(1c). Thus, the neutraceutical Caiapo seems to be a useful agent in the treatment of type 2 diabetes.     

A new alpha-glucosidase inhibitor (Bay-m-1099) reduces insulin requirements with meals in insulin-dependent diabetes mellitus

Retardation of meal carbohydrate absorption by inhibition of starch degradation improves glucose tolerance in normal and diabetic humans. To determine the effects of Bay-m-1099, a new alpha-glucosidase inhibitor, on insulin requirements and prandial glucose tolerance in patients with insulin-dependent diabetes mellitus (IDDM), plasma glucose, triglyceride, and free insulin concentrations were measured after ingestion of a standard breakfast, lunch, and dinner in nine patients with IDDM in a single-blind, randomized, crossover design. A 20% reduction in insulin was given 30 minutes before the meals when the subjects received Bay-m-1099 (50 mg). This resulted in the AUC for plasma insulin to be significantly less with Bay-m-1099 (AUC, 8.2 +/- 1.3 vs. 12.8 +/- 1.6 microU/ml/min with placebo; P less than 0.01). Despite this reduction in plasma insulin levels, postprandial plasma glucose concentrations were reduced for the breakfast (73 +/- 15 vs. 112 +/- 14 mg/dl/min with placebo; P less than 0.01) and dinner (23 +/- 8 vs. 4 +/- 1 mg/dl/min with placebo; P less than 0.05) meal with Bay-m-1099. Bay-m-1099 did not affect postprandial plasma triglycerides and was well tolerated, the major side effect being flatulence (4/9) and mild diarrhea (4/9). We conclude that inhibition of intestinal alpha-glucosidases by Bay-m-1099 in IDDM reduces meal insulin requirements by at least 20% and that such an agent could be useful in the management of diabetes mellitus by reducing hyperinsulinemia.     

Metabolic response to fasting exercise in adolescent insulin-dependent diabetic subjects treated with continuous subcutaneous insulin infusion and intensive conventional therapy

The metabolic effects of moderate exercise in the fasting state were examined in 12 insulin-dependent diabetic adolescents treated with continuous subcutaneous insulin infusion (CSII) or intensive conventional therapy (ICT). Six patients received their usual afternoon dose the evening before the study and six received their usual infusion rate during exercise. Insulin was injected subcutaneously in the abdominal wall. Exercise was performed on a bicycle ergometer for 45 min at 50% maximum oxygen consumption. Resting plasma glucose values during both CSII (114 +/- 18 mg/dl, P less than 0.02) and ICT (136 +/- 30 mg/dl, P less than 0.01) were higher than normal (77 +/- 11 mg/dl). Diabetic patients receiving CSII showed a sharp decrease in glycemia after 45 min of exercise (77 +/- 18 mg/dl, P less than 0.02). In contrast, in patients receiving ICT and in control subjects plasma glucose did not change during exercise or recovery. Insulin levels decreased significantly during exercise in the control subjects while there was no change in plasma free insulin levels during exercise in the diabetic subjects. Profiles of intermediary metabolites in response to exercise were similar in all groups with no significant differences in resting values between diabetic subjects and controls. Continuous subcutaneous insulin infusion provides near-normoglycemia in the insulin-dependent diabetic adolescent. However, with the basal insulin infusion rate necessary to achieve near-normal fasting blood glucose levels, moderate exercise in the postabsorptive state may result in hypoglycemia with CSII.     

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.     

Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine

OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo-controlled crossover trial with 1-wk treatment periods (2 x 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U.kg-1.h-1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U.kg-1.h-1) insulin delivery rates. RESULTS: In the nondiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (-1.2 +/- 0.5 kg, P less than 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 +/- 0.8 vs. 9.4 +/- 1.1 mM, P less than 0.005) and plasma free fatty acid concentrations (1150 +/- 227 vs. 1640 +/- 184 microM, P less than 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after d-fenfluramine (average increase of glucose MCR 35 +/- 12%, P less than 0.02). CONCLUSIONS: Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.     

Bromocriptine: a novel approach to the treatment of type 2 diabetes

OBJECTIVE: In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment. RESULTS: No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group. CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.     

Plasma glucose concentrations during liver transplantation

We reviewed the intraoperative plasma glucose concentrations in 100 consecutive patients who underwent orthotopic liver transplantation. The plasma glucose concentration increased significantly (P less than 0.05) from 110 +/- 46 mg/dl (mean +/- SD) to 204 +/- 60 mg/dl during the preanhepatic phase of transplantation (phase I). No significant change in plasma glucose concentrations occurred during the anhepatic phase (phase II). During the reperfusion phase (phase III), the mean plasma glucose concentration increased significantly (P less than 0.05) from 201 +/- 56 mg/dl to 384 +/- 72 mg/dl. The only glucose administered was that contained in the blood products. No correlation was found between the amount of glucose administered with the blood products and the changes in plasma glucose concentrations in these patients. None of the patients became hypoglycemic during any phase of the transplant procedure. All patients demonstrated a tendency toward hyperglycemia.     

Increased symptoms of hypoglycaemia in the standing position in insulin-dependent diabetes mellitus.

1. To test the hypothesis that patients with insulin-dependent diabetes mellitus perceive the symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position, we assessed symptoms of hypoglycaemia, as well as heart rate and plasma noradrenaline and adrenaline concentrations, in both positions during hyperinsulinaemic glucose clamps on three occasions in seven patients. 2. Plasma glucose concentrations were clamped at 5.0 mmol/l (90 mg/dl) and 5.0 mmol/l on one occasion, at 5.0 mmol/l and 3.9 mmol/l (70 mg/dl) on another occasion, and at 5.0 mmol/l and 2.8 mmol/l (50 mg/dl) on yet another occasion. 3. During euglycaemia there was no effect of position on the symptom panels used to assess the symptomatic response to hypoglycaemia. However, at the plasma glucose concentration of 2.8 mmol/l, total (P less than 0.003) and neurogenic (P less than 0.005), but not neuroglycopenic, hypoglycaemic symptom scores were higher with the patients in the standing than in the lying position. Increments in total hypoglycaemic symptom scores, over those during the corresponding euglycaemic phase, were 5 +/- 2 in the lying position and 11 +/- 2 in the standing position (means +/- SEM, P less than 0.01). 4. Thus patients with insulin-dependent diabetes mellitus perceive symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position because of enhanced neurogenic symptoms.     

Effect of insulin-glucose infusions on plasma glucagon levels in fasting diabetics and nondiabetics.

The effect of the intravenous infusion of insulin plus glucose on plasma glucagon levels was studied in hyperglycemic fasting adult-type and juvenile-type diabetics and compared with fasting nondiabetics. Adult-type diabetics were given insulin for 2 h at a rate of 0.03 U/kg-min, raising their mean insulin to between 25 and 36 muU/ml; glucagon declined from a base-line value of 71+/-2 (SEM) to 56+/-1 pg/ml at 120 min (P less than 0.001). In juvenile-type diabetics given the same insulin-glucose infusion, glucagon declined from a base-line level of 74+/-8 to 55+/-5 pg/ml at 120 min (P less than 0.05). The absolute glucagon values in the diabetic groups did not differ significantly at any point from the mean glucagon levels in nondiabetics given insulin at the same rate plus enough glucose to maintain normoglycemia. When glucagon was expressed as percent of baseline, however, the normoglycemic nondiabetics exhibited significantly lower values than adult-type diabetics at 90 and 120 min and juvenile-type diabetics at 60 min. In nondiabetics given insulin plus glucose at a rate that caused hyperglycemia averaging between 134 and 160 mg/dl, glucagon fell to 41+/-7 pg/ml at 120 min, significantly below the adult diabetics at 90 and 120 min (P less than 0.01 and less than 0.05) and the juvenile group at 60 min (P less than 0.01). The mean minimal level of 39+/-2 pg/ml was significantly below the adult (P less than 0.001) and juvenile groups (P less than 0.05). When insulin was infused in the diabetic groups at a rate of 0.4 U/kg-min together with glucose, raising mean plasma insulin to between 300 and 600 muU/ml, differences from the hyperglycemic nondiabetics were no longer statistically significant. It is concluded that, contrary to the previously reported lack of insulin effect in diabetics during carbohydrate meals, intravenous administration for 2 h of physiologic amounts of insulin plus glucose is accompanied in unfed diabetics by a substantial decline in plasma glucagon. These levels are significantly above hyperglycemic nondiabetics at certain points but differ from normoglycemic nondiabetics only when expressed as percent of the baseline. At a supraphysiologic rate of insulin infusion in diabetics, these differences disappear.     

Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.

To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.     

Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone

OBJECTIVE: To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 23 diabetic patients (age 30-70 years BMI < 36 kg/m2) who being treated with a stable dose of sulfonylurea were randomly assigned to receive either placebo (n = 11) or pioglitazone (45 mg/day) (n = 12) for 16 weeks. Before and after 16 weeks of treatment, all subjects received a 75-g oral glucose tolerance test (OGTT) and hepatic peripheral insulin sensitivity was measured with a two-step euglycemic insulin (40 and 160 mU x min(-1) x m(-2) clamp performed with 3-[3H]glucose and indirect calorimetry HbA1c measured monthly throughout the study period. RESULTS: After 16 weeks of pioglitazone treatment, the fasting plasma glucose (FPG; 184 +/- 15 to 135 +/- 11 mg/dl, P < 0.01), mean plasma glucose during OGTT(293 +/- 12 to 225 +/- 14 mg/dl, P < 0.01), and HbA1c (8.9 +/- 0.3 to 7.2 +/- 0.5%, P < 0.01 ) decreased significantly without change in fasting or glucose-stimulated insulin/C-peptide concentrations. Fasting plasma free fatty acid (FFA; 647 +/- 39 to 478 +/- 49) microEq/l, P < 0.01) and mean plasma FFA during OGTT (485 +/- 30 to 347 +/- 33 microEq/l, P < 0.01) decreased significantly after pioglitazone treatment. Before and after pioglitazone treatment, basal endogenous glucose prodution (EGP) and FPG were strongly correlated (r = 0.67, P < 0.01). EGP during the first insulin clamp step was significantly decreased after pioglitazone treatment (P < 0.05) whereas insulin-stimulated total and nonoxidative glucose disposal during the second insulin clamp was increased (P < 0.01). The change in FPG was related to the change in basal EGP, EGP during the first insulin clamp step, and total glucose disposal during the second insulin clamp step. The change in mean plasma glucose concentration during the OGGTT was strongly related to the change in total body glucose disposl during the second insulin clamp step. CONCLUSIONS: These results suggest that pioglitazone therapy in type 2 diabetic patients decreases lasting and postprandial plasma glucose levels by improving hepatic and peripheral (muscle) tissue sensitivity to insulin.     

Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM.

OBJECTIVE: To study the effects of CS-045, a newly developed thiazolidine analogue, on glucose tolerance and insulin response to oral glucose load in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Nineteen NIDDM patients (mean +/- SD age 48.9 +/- 9.4 yr) whose previous glycemic control on diet and/or sulfonylurea (SU) therapy was judged stable but unsatisfactory (greater than 7.8 mM) were selected for this study. CS-045 (400 mg/day p.o.) was given alone or together with the previous SU drugs for 12 wk. A 75-g oral glucose tolerance test (OGTT) was performed before and after CS-045 treatment. Results: The following results were found after CS-045 treatment. 1) Fasting plasma glucose (FPG) and HbA1c decreased (n = 19, FPG, 11.0 +/- 2.4 vs. 8.4 +/- 2.7 mM [before vs. after], P less than 0.001; HbA1c, 8.0 +/- 1.1 vs. 7.4 +/- 1.3%, P less than 0.005), and glucose tolerance markedly improved. 2) Fasting insulin (immunoreactive insulin [IRI]) and insulin response during OGTT decreased (n = 19, fasting IRI, 77.4 +/- 49.8 vs. 56.5 +/- 24.6 pM [before vs. after], P less than 0.05; area under the curve of IRI, 540.3 +/- 350.5 vs. 426.4 +/- 216.3 pM.h, P less than 0.05). CONCLUSIONS: CS-045 is effective in improving glucose tolerance without stimulation of insulin secretion in NIDDM, suggesting an effect in improving insulin sensitivity.     

Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes.

The changes in hepatic glucose production (Ra), tissue glucose disposal (Rd), and plasma glucose and insulin concentration that took place over a 16-h period from 10 to 2 p.m. were documented in 14 individuals; 8 with non-insulin-dependent diabetes mellitus (NIDDM) and 6 with normal glucose tolerance. Values for Ra were higher than normal in patients with NIDDM at 10 p.m. (4.73 +/- 0.41 vs. 3.51 +/- 0.36 mg/kg per min, P less than 0.001), but fell at a much faster rate throughout the night than that seen in normal subjects. As a consequence, the difference between Ra in normal individuals and patients with NIDDM progressively narrowed, and by 2 p.m., had ceased to exist (1.75 +/- 0.61 vs. 1.67 +/- 0.47 mg/kg per min, P = NS). Plasma glucose concentration also declined in patients with NIDDM over the same period of time, but they remained quite hyperglycemic, and the value of 245 +/- 27 mg/dl at 2 p.m. was about three times greater than in normal individuals. Plasma insulin concentrations also fell progressively from 10 to 2 p.m., and were similar in both groups throughout most of the 16-h study period. Thus, the progressive decline in Ra in patients with NIDDM occurred despite concomitant falls in both plasma glucose and insulin concentration. Glucose disposal rates also fell progressively in both groups, but the magnitude of the fall was greater in patients with NIDDM. Consequently, Rd in patients with NIDDM was higher at 10 p.m. (3.97 +/- 0.48 vs. 3.25 +/- 0.13 mg/kg per min, P less than 0.001) and lower the following day at 2 p.m. (1.64 +/- 0.21 vs. 1.97 +/- 0.35 mg/kg per min, P less than 0.01). These results indicate that a greatly expanded pool size can exist in patients with NIDDM at a time when values for Ra are identical to those in normal subjects studied under comparable conditions, which suggests that fasting hyperglycemia in NIDDM is not simply a function of an increase in Ra.