Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin

OBJECTIVE: To evaluate further the relative roles played by liver and adipose tissue in the therapeutic response to metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 11 patients with diet-treated type 2 diabetes were given metformin for approximately 3 months. Measurements were made before and after treatment of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance (Ra) and disappearance (Rd) rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 195-min infusion period at relatively low insulin (approximately 12-24 microU/ml) concentrations. RESULTS: Mean +/- SEM fasting plasma glucose concentration was significantly lower (175 +/- 11 vs. 224 +/- 15 mg/dl; P < 0.01) after treatment with metformin. Mean +/- SEM insulin concentrations measured from 8:00 A.M. to 5:00 P.M. did not change with treatment. However, both glucose and FFA concentrations were significantly lower (P < 0.01) when measured over the same time period, and the decreases in plasma FFA and glucose concentration were highly correlated (r = 0.81; P = 0.03). Overnight glucose turnover studies indicated that neither Ra (hepatic glucose production [HGP]) nor Rd changed significantly with treatment in association with metformin treatment. Since plasma glucose concentration was much lower after metformin treatment, the overnight glucose metabolic clearance rate (MCR) was significantly lower (P < 0.01). Finally, the ability of insulin to inhibit isoproterenol-stimulated increases in plasma FFA concentration was enhanced in metformin-treated patients (P < 0.05). CONCLUSIONS: Metformin treatment was associated with significantly lower fasting plasma glucose concentrations and lower day-long plasma glucose and FFA concentrations. Although overnight HGP was unchanged after treatment with metformin, the overnight glucose MCR was significantly increased, and the antilipolytic activity of insulin was also enhanced. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to a decrease in release of FFA from adipose tissue, leading to lower circulating FFA concentrations and an increase in glucose uptake.     

Alterations in glucose metabolism in the elderly patient with diabetes

OBJECTIVE: To determine the alterations in glucose metabolism in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: We studied 9 healthy elderly control subjects (73 +/- 1 yr of age; body mass index 25.7 +/- 0.4 kg/m2) and 9 untreated elderly NIDDM patients (72 +/- 2 yr of age; BMI 25.9 +/- 0.5 kg/m2). Each subject underwent a 3-h oral glucose tolerance test (40 g/m2); a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above basal); and a 4-h euglycemic insulin clamp (40 mM.m2.min-1). Tritiated glucose methodology was used to measure glucose production and disposal rates during the euglycemic clamp. RESULTS: Patients with NIDDM had a higher fasting glucose (9.3 +/- 0.3 vs. 5.1 +/- 0.1 mM in control subjects vs. NIDDM patients, respectively, P < 0.001) and a greater area under the curve for glucose during the OGTT (16.0 +/- 0.6 vs. 6.7 +/- 0.3 mM in control subjects vs. NIDDM patients, respectively, P < 0.01) than the healthy control subjects. During the hyperglycemic clamp, patients with NIDDM had an absent first-phase insulin response (112 +/- 6 vs. 250 +/- 31 pM in control subjects vs. NIDDM patients, respectively, P < 0.01), and a blunted second-phase insulin response (159 +/- 11 vs. 337 +/- 46 pM in control subjects vs. NIDDM patients, respectively, P < 0.01). Before the euglycemic clamp, fasting insulin (99 +/- 5 vs. 111 +/- 10 pM in control subjects vs. NIDDM patients, respectively) and hepatic glucose production (11.8 +/- 0.7 vs. 11.5 +/- 0.5 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively) were similar. Steady-state (180-240 min) glucose disposal rates during the euglycemic clamp were slightly, but not significantly, higher in the normal control subjects (36.5 +/- 1.1 vs. 33.1 +/- 1.9 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively, NS). CONCLUSIONS: We conclude that NIDDM in nonobese elderly subjects is characterized by a marked impairment in insulin release. This may be attributable to the toxic effects of chronic hyperglycemia on the beta-cell. When compared with age-matched control subjects, the NIDDM patients showed no increase in fasting insulin or hepatic glucose production, and insulin resistance was mild.     

Overnight normalization of glucose concentrations improves hepatic but not extrahepatic insulin action in subjects with type 2 diabetes mellitus

Subjects with poorly controlled type 2 diabetes are both hyperglycemic and insulin resistant. To determine whether short term restoration of normoglycemia improves insulin action, hyperinsulinemic (approximately 300 pmol/L) euglycemic clamps were performed in diabetic subjects after either overnight infusion of saline or overnight infusion of insulin in amounts sufficient to maintain euglycemia throughout the night. Fasting glucose concentrations (5.2 +/- 0.2 vs. 11.9 +/- 1.4 mmol/L; P < 0.01) and rates of endogenous glucose production (13.0 +/- 1.1 vs. 18.6 +/- 1.6 mumol/kg.min; P < 0.05) were both lower after overnight insulin than overnight saline. Insulin-induced stimulation of glucose uptake (to 34.9 +/- 6.8 vs. 28.8 +/- 3.4 mumol/kg.min; P = 0.2) and inhibition of free fatty acids (to 0.13 +/- 0.03 vs. 0.12 +/- 0.04 mmol/L; P = 0.6) did not differ after overnight saline and overnight insulin. In contrast, endogenous glucose production during the final hour of the hyperinsulinemic clamps (i.e. when glucose concentrations were the same) remained higher (P = 0.05) after overnight saline than after overnight insulin (5.5 +/- 1.5 vs. 0.02 +/- 1.4 mumol/kg.min). Thus, acute restoration of euglycemia by means of an overnight insulin infusion improves hepatic (and perhaps renal) but not extrahepatic insulin action.     

Glucose and amino acid turnover in untreated gestational diabetes

OBJECTIVE: Although gestational diabetes affects as many as 3% of all pregnant women, specific aspects of glucose and protein metabolism in this population have not been clearly delineated. We tested the hypothesis that gestational diabetes mellitus (GDM) results in increased glucose production and proteolysis during fasting. RESEARCH DESIGN AND METHODS: Using tracer isotope infusions, the rate of appearance (Ra) of glucose, leucine, phenylalanine and tyrosine, phenylalanine hydroxylation, leucine oxidation, and urea nitrogen excretion were determined after an overnight fast in 10 GDM subjects, within 2 weeks of diagnosis and before initiation of treatment, and in a matched control group of nine healthy nondiabetic pregnant women. RESULTS: Fasting glucose Ra was similar in GDM patients and control subjects (GDM, 12.8 +/- 1.1 vs. control subjects, 12.8 +/- 0.9 mumol . kg-1 . min-1). Leucine and phenylalanine Ra (reflecting proteolysis) also were not different between GDM patients and control subjects (GDM leucine Ra, 128 +/- 14 vs. control subjects, 124 +/- 5; phenylalanine Ra GDM, 35 +/- 4 vs. control subjects, 40 +/- 2 mumol . kg-1 . h-1). Furthermore, leucine oxidation and phenylalanine hydroxylation were not increased in GDM subjects, urea nitrogen excretion was actually lower in GDM patients. However, fasting insulin concentrations were significantly elevated in GDM subjects (GDM, 165 +/- 35 vs. control subjects, 30 +/- 5 pmol/l; P < 0.01). CONCLUSIONS: Hepatic glucose release and whole-body proteolysis in GDM patients were remarkably similar to matched pregnant control subjects. This was achieved with insulin concentrations three- to fivefold higher than normal, suggesting significant insulin resistance for both glucose and protein metabolism in GDM.     

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.     

Intracellular glucose metabolism after long term metabolic control with glyburide: improved glucose oxidation with unchanged glycogen synthase activity

To determine whether improved metabolic control with long term glyburide treatment alters intracellular glucose metabolism independent of effects on glucose uptake (GU), we studied eight obese patients with noninsulin-dependent diabetes mellitus before and 7 months after glyburide therapy. Indirect calorimetry and skeletal muscle biopsies were performed in the basal state and during 300 pmol/m2.min insulin infusions, with glucose turnover rates determined by [3-3H]glucose turnover. During the glucose clamps, rates of GU were matched before and after treatment using equivalent hyperinsulinemia and variable levels of hyperglycemia. After glyburide treatment, rates of GU were decreased in the basal state [4.16 +/- 0.57 vs. 3.29 +/- 0.37 mg/kg fat free mass (FFM)/min; P < 0.05], but similar during glucose clamps (11.53 +/- 1.42 vs. 11.93 +/- 1.32 mg/kg FFM.min; P = NS) according to study design. In both the basal state and during glucose clamps after glyburide therapy, rates of glucose oxidative metabolism (Gox) increased by 68-78% [1.21 +/- 0.16 vs. 2.03 +/- 0.31 mg/kg FFM.min (P < 0.05) and 3.13 +/- 0.51 vs. 5.58 +/- 0.55 mg/kg FFM.min (P < 0.05), respectively], and rates of nonoxidative glucose metabolism decreased [2.96 +/- 0.68 vs. 1.25 +/- 0.21 mg/kg FFM.min (P < 0.05) and 8.40 +/- 1.50 to 6.30 +/- 1.40 mg/kg FFM.min (P < 0.01), respectively]. Circulating plasma FFA levels and rates of fat oxidation (Fox) remained unchanged in both the basal state and during clamp studies. Skeletal muscle glycogen synthase (GS) activity, expressed as fractional velocity, was unchanged by glyburide therapy (2.2 +/- 0.8 vs. 2.7 +/- 0.3% in the basal state and 7.3 +/- 1.8 vs. 6.1 +/- 0.9% during clamps; both P = NS). In summary, at both matched (during clamp studies) and unmatched (during basal studies) rates of GU, improved metabolic control with glyburide therapy resulted in marked improvement of Gox independent of the effects on GU. The improvement in Gox was not associated with changes in Fox, circulating FFA, or muscle GS activity. These data indicate that long term metabolic control achieved by glyburide therapy markedly improves Gox, but not skeletal muscle GS activity, in noninsulin-dependent diabetes mellitus independent of GU and Fox.     

Glucose production, utilization, and cycling in response to moderate exercise in obese subjects with type 2 diabetes and mild hyperglycemia

The glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.     

Effect of pravastatin treatment on glucose, insulin, and lipoprotein metabolism in patients with hypercholesterolemia

Treatment of patients with type IIA hyperlipoproteinemia (HLP) with pravastatin for 3 months led to significant decreases (p < 0.001) in total cholesterol (7.18 +/- 0.30 to 5.75 +/- 0.30 mmol/L), LDL cholesterol (5.56 +/- 0.33 to 4.02 +/- 0.32 mmol/L), and ratio of total cholesterol to HDL cholesterol (6.5 +/- 0.4 to 4.6 +/- 0.4). Decreases of a similar magnitude were also seen in patients with type IIB HLP. Plasma glucose and insulin concentrations after an oral glucose load and from 8 AM to 4PM in response to meals were higher in patients with Type IIB HLP, who also had higher steady-state plasma glucose concentrations after an infusion of somatostatin, insulin, and glucose (12.4 +/- 1 vs 5.5 +/- 0.8 mmol/L, p < 0.001). Because steady-state plasma insulin concentrations were similar in both groups, patients with type IIB HLP were relatively insulin resistant. Furthermore, day-long plasma glucose concentrations and insulin resistance were modestly, but significantly (p < 0.01), greater after treatment in both groups. In conclusion, LDL cholesterol metabolism improved in hypercholesterolemic subjects treated with pravastatin, but the hypertriglyceridemia, insulin resistance, relative glucose intolerance, and hyperinsulinemia present in patients with type IIB HLP either did not improve with treatment or was somewhat worse.     

Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas

OBJECTIVE: To investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg-1.min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m2, mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS: GLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 +/- 0.4 and 4.5 +/- 0.1 vs. 6.0 +/- 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 +/- 60 vs. 724 +/- 91 mmol.l-1. min-1, area under the curve [AUC] [-30-180 min], P < 0.02), whereas glibenclamide had no effect (598 +/- 101 mmol.l-1. min-1, AUC [-30-180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 +/- 24 mmol. l-1.min, AUC [-30-180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 +/- 0.4; GLP-I 6.3 +/- 1.6, P < 0.01; glibenclamide 6.8 +/- 2.1, P < 0.01; combination 20.7 +/- 5.0, P < 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50% compared with the control subjects (P < 0.01). CONCLUSIONS: In acute experiments on overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.     

Optimization of evening insulin dose in patients using the short-acting insulin analog lispro

OBJECTIVE: A three-way, crossover, open-label, randomized study was designed to compare the evening and night (1800-0800) glycemic control when the evening premeal lispro dose was reduced by 20% and the bedtime basal NPH dose increased by 25%, or when the basal NPH dose was moved to before dinner at 1800, compared with the control arm on standard premeal human regular insulin and pre-bedtime NPH insulin. RESEARCH DESIGN AND METHODS: A total of 13 type 1 diabetic patients who use a premeal plus basal insulin regimen were studied on three separate days, with identical meals and snacks at the same times on each study day. On the control study day, patients received human regular insulin before dinner and NPH at bedtime in their usual doses. On another day, lispro was given before dinner with a dose reduction of 20%, and NPH at bedtime at 125% of usual dose. In the third regimen, the lispro and NPH were administered together in their usual dose before the evening meal by separate injections. The three regimens were tested in random order. RESULTS: Postprandial (1800-2200) blood glucose concentrations were lower after reduced-dose lispro compared with human regular insulin (6.0 +/- 0.3 [SEM] vs. 7.4 +/- 0.3 mmol/l, P < 0.05). Nighttime (2400-0400) blood glucose concentrations were not different (8.6 +/- 0.3 vs. 9.2 +/- 0.3 mmol/l, NS), and prebreakfast concentrations were also unchanged (7.7 +/- 0.9 vs. 8.7 +/- 0.8 mmol/l) after lispro with increased-dose NPH compared with standard insulin. By contrast, both nighttime (10.0 +/- 0.3 mmol/l, P < 0.05) and fasting glucose concentrations (10.8 +/- 0.6 mmol/l, P < 0.05) were significantly higher with dinnertime usual-dose lispro plus dinnertime usual-dose NPH compared with standard human insulin. Hypoglycemia at night (blood glucose < 3.0 mmol/l) did not differ between study days, but it was more frequent postprandially after dinner usual-dose lispro plus early NPH (2 vs. 7 patients, P = 0.062). CONCLUSIONS: With lower mealtime and higher basal bedtime insulin doses, patients using insulin lispro may be able to gain an overall improvement in evening blood glucose control without deteriorated nighttime glucose levels. Earlier basal NPH dosage alone does not ameliorate the nighttime hyperglycemia of short-acting insulin analog regimens.     

Hyperamylinemia is associated with hyperinsulinemia in the glucose-tolerant, insulin-resistant offspring of two Mexican-American non-insulin-dependent diabetic parents

Several investigations have presented evidence that amylin inhibits insulin secretion and induces insulin resistance both in vitro and in vivo. However, basal and postmeal amylin concentrations proved similar in non-insulin-dependent diabetes mellitus (NIDDM) patients and controls. Since hyperglycemia may alter both amylin and insulin secretion, we examined basal and glucose-stimulated amylin secretion in eight glucose-tolerant, insulin-resistant Mexican-American subjects with both parents affected with NIDDM (offspring) and correlated the findings with the insulin sensitivity data acquired by an insulin clamp. Eight offspring and eight Mexican-Americans without any family history of diabetes (controls) underwent measurement of fat free mass (3H2O dilution method), 180-minutes, 75-g oral glucose tolerance test (OGTT), and 40-mU/m2, 180-minute euglycemic insulin clamp associated with 3H-glucose infusion and indirect calorimetry. Fasting amylin was significantly increased in offspring versus controls (11.5 +/- 1.4 v 7.0 +/- 0.8 pmol/L, P < .05). After glucose ingestion, both total (3,073 +/- 257 v 1,870 +/- 202 pmol.L-1.min-1, P < .01) and incremental (1,075 +/- 170 v 518 +/- 124 pmol.L-1.min-1, P < .05) areas under the curve (AUCs) of amylin concentration were significantly greater in offspring. The amylin to insulin molar ratio was similar in offspring and controls at all time points. Basal and postglucose insulin and C-peptide concentrations were significantly increased in the offspring. No correlation was found between fasting amylin, postglucose amylin AUC or IAUC, and any measured parameter of glucose metabolism during a euglycemic-hyperinsulinemic clamp (total glucose disposal, 7.21 +/- 0.73 v 11.03 +/- 0.54, P < .001; nonoxidative glucose disposal, 3.17 +/- 0.59 v 6.33 +/- 0.56, P < .002; glucose oxidation, 4.05 +/- 0.46 v 4.71 +/- 0.21, P = NS; hepatic glucose production, 0.29 +/- 0.16 v 0.01 +/- 0.11, P = NS; all mg.min-1.kg-1 fat-free mass, offspring v controls). In conclusion, these data do not support a causal role for amylin in the genesis of insulin resistance in NIDDM.     

Normal glucose-induced suppression of glucose production but impaired stimulation of glucose disposal in type 2 diabetes: evidence for a concentration-dependent defect in uptake

The present studies were undertaken to determine whether people with type 2 diabetes are resistant to the effects of glucose as well as insulin. Diabetic and nondiabetic subjects were studied on three occasions. Hormone secretion was inhibited with somatostatin. Insulin concentrations were kept at "basal" levels (referred to as low insulin infusion) from 0 to 180 min then increased to approximately 200 pmol/l from 181 to 360 min (referred to as high insulin infusion). Glucose concentrations were clamped at either approximately 95, approximately 130, or approximately 165 mg/dl on each occasion. In the presence of basal insulin concentrations, a progressive increase in glucose from 95 to 130 to 165 mg/dl was accompanied by a comparable and progressive decrease (P = 0.001 to 0.003 by analysis of variance [ANOVA]) in endogenous glucose production (measured with [6-(3)H]glucose) and total glucose output (measured with [2-(3)H]glucose) and incorporation of 14CO2 into glucose (an index of gluconeogenesis) in both diabetic and nondiabetic subjects, indicating normal hepatic (and perhaps renal) response to glucose. In the nondiabetic subjects, an increase in glucose concentration from 95 to 130 to 165 mg/dl resulted in a progressive increase in glucose disappearance during both the low (19.9 +/- 1.8 to 23.6 +/- 1.8 to 25.4 +/- 1.6 micromol x kg(-1) x min(-1); P = 0.003 by ANOVA) and high (36.4 +/- 3.1 to 47.6 +/- 4.5 to 61.1 +/- 7.0 micromol x kg(-1) x min(-1); P = 0.001 by ANOVA) insulin infusions. In contrast, in the diabetic subjects, whereas an increase in glucose from 95 to 130 mg/dl resulted in an increase in glucose disappearance during both the low (P = 0.001) and high (P = 0.01) dose insulin infusions, a further increase in glucose concentration to 165 mg/dl had no further effect (P = 0.41 and 0.38) on disappearance at either insulin dose (low: 14.2 +/- 0.8 to 18.2 +/- 1.1 to 18.7 +/- 2.4 micromol x kg(-1) x min(-1); high: 21.0 +/- 3.2 to 33.9 +/- 6.4 to 32.5 +/- 8.0 micromol x kg(-1) x min(-1) for 95, 130, and 165 mg/dl, respectively). We conclude that whereas glucose-induced stimulation of its own uptake is abnormal in type 2 diabetes, glucose-induced suppression of endogenous glucose production and output is not. The abnormality in uptake occurs in the presence of both basal and high insulin concentrations and is evident at glucose concentrations above but not below 130 mg/dl, implying a defect in a glucose-responsive step.     

Measurement of platelet aggregation peptide inhibitors by ultrasonic interferometry

In healthy subjects, basal hepatic glucose production is (partly) regulated by paracrine intrahepatic factors. It is unknown if these paracrine factors also influence basal glucose production in infectious diseases with increased glucose production. We compared the effects of 150 mg indomethacin (n = 9), a nonendocrine stimulator of glucose production in healthy adults, and placebo (n = 7) on hepatic glucose production in Vietnamese adults with uncomplicated falciparum malaria. Glucose production was measured by primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, the plasma glucose concentration and glucose production increased in all subjects from 5.3 +/- 0.1 mmol/L to a maximum of 7.1 +/- 0.3 mmol/L (P < .05) and from 17.6 +/- 0.8 micromol x kg(-1) x min(-1) to a maximum of 26.2 +/- 2.5 micromol x kg(-1) x min(-1) (P < .05), respectively. In the control group, the plasma glucose concentration and glucose production declined gradually during 4 hours from 5.4 +/- 0.2 mmol/L to 5.1 +/- 0.1 mmol/L (P < .05) and from 17.1 +/- 0.8 micromol x kg(-1) x min(-1) to 15.1 +/- 1.0 micromol x kg(-1) x min(-1) (P < .05), respectively. There were no differences in plasma concentrations of insulin, counterregulatory hormones, or cytokines between the groups. We conclude that indomethacin administration results in a transient increase in glucose production in patients with uncomplicated falciparum malaria in the absence of changes in plasma concentrations of glucoregulatory hormones or cytokines. Thus, this study indicates that in uncomplicated falciparum malaria, the rate of basal hepatic glucose production is also regulated by paracrine intrahepatic factors.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Transport of paraquat by isolated renal proximal tubular segments from rabbits

In order to evaluate somatostatin (SRIH) secretion in uremia, plasma SRIH concentrations were determined in basal conditions and after an oral glucose tolerance test (OGTT) in 14 non-dialysed patients with chronic renal failure (CRF), seven of whom had normal glucose tolerance (NGT) and seven impaired glucose tolerance (IGT). Plasma insulin, C-peptide and glucagon and blood glucose concentrations were also evaluated. The results were compared with those obtained in a group of age- and sex-matched normal subjects. In CRF patients, plasma SRIH fasting values (8.6 +/- 0.6 and 7.8 +/- 0.6 pmol/L in NGT and IGT patients, respectively) were comparable to those recorded in controls (7.7 +/- 0.5 pmol/L). SRIH response to OGTT, evaluated as area under curves (AUC) above basal, was similar in both groups of CRF patients (412.9 +/- 84.5 and 415.6 +/- 51.9 pmol/L per min), and significantly lower than in controls (660.1 +/- 58.5 pmol/L per min). Data indicate that chronic uremia induces a loss of SRIH secretory cell responsiveness to glucose. A possible effect of impaired SRIH secretion on glucose metabolism in CRF is discussed.     

The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients

The effect of metformin therapy on glucose metabolism was examined in eight overweight newly presenting untreated type II diabetic patients (five males, three females). Patients were treated for 12 weeks with either metformin (850 mg x 3) or matching placebo using a double-blind crossover study design; patients were studied at presentation and at the end of each treatment period. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) before and during a 4-hour hyperinsulinemic euglycemic clamp (100 mU.kg-1 x h-1). Metformin therapy was associated with a significant decrease in fasting blood glucose (6.8 +/- 0.6 v 8.3 +/- 0.9 mmol.L-1, P < .01) and glycosylated hemoglobin ([HbA1] 7.7% +/- 0.4% v 8.5% +/- 0.5%, P < .01) levels. Fasting hepatic glucose production (HGP) was also significantly decreased following metformin therapy (1.98 +/- 0.13 v 2.41 +/- 0.20 mg.kg-1 x min-1, P < .02), whereas fasting insulin and C-peptide concentrations remained unaltered. The decrease in basal HGP correlated closely with the decrease in fasting blood glucose concentration (r = .92, P < .001). Insulin-stimulated glucose uptake was assessed using the hyperinsulinemic euglycemic clamp technique and was increased post-metformin (3.8 +/- 0.6 v 3.1 +/- 0.7 mg.kg-1 x min-1, P < .05). This was primarily the result of increased nonoxidative glucose metabolism (1.1 +/- 0.6 v 0.4 +/- 0.6 mg.kg-1 x min-1, P < .05); oxidative glucose metabolism did not change. Metformin had no measurable effect on insulin activation of skeletal muscle GS, the rate-limiting enzyme controlling muscle glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat

Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, peripheral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old male Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or moderately calorie restricted (18 CR) up to 18 mo of age. Total fat mass (FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged. Most important, 18 CR had more FM (65+/-6 vs. 45+/-6 g) but less VF (7.8+/-0.6 vs. 12.3+/-3.3 g) compared with 4 AL (P < 0.01 for both). Thus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of young rats, while peripheral insulin sensitivity remained unchanged (by insulin clamp of 18 mU/kg/min). In fact, the rates of insulin infusion required to maintain basal hepatic glucose production in the presence of pancreatic clamp were 0.75+/-0.10, 1.41+/-0.13, and 0.51+/-0.12 mU/kg . min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreased by 32% (P < 0. 005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin resistance was induced. We propose that in this animal model the age-associated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin resistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate metabolism in aging.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Acute non-insulin-like stimulation of rat muscle glucose metabolism by troglitazone in vitro

1. The direct short-term effects of troglitazone on parameters of glucose metabolism were investigated in rat soleus muscle strips. 2. In muscle strips from Sprague-Dawley rats, troglitazone (3.25 micromol l(-1)) increased basal and insulin-stimulated glucose transport by 24% and 41%, respectively (P<0.01 each). 3. In the presence of 5 nmol l(-1) insulin, stimulation of glucose transport by 3.25 micromol l(-1) troglitazone was accompanied by a 36% decrease in glycogen synthesis, while glycolysis was increased (112% increase in lactate production) suggesting a catabolic response of intracellular glucose handling. 4. Whereas insulin retained its stimulant effect on [3H]-2-deoxy-glucose transport in hypoxia-stimulated muscle (by 44%; c.p.m. mg(-1) h(-1): 852+/-77 vs 1229+/-75, P<0.01), 3.25 micromol l(-1) troglitazone failed to increase glucose transport under hypoxic conditions (789+/-40 vs 815+/-28, NS) suggesting that hypoxia and troglitazone address a similar, non-insulin-like mechanism. 5. No differences between troglitazone and hypoxia were identified in respective interactions with insulin. 6. Troglitazone acutely stimulated muscle glucose metabolism in a hypoxia/contraction-like manner, but it remains to be elucidated whether this contributes to the long-term antidiabetic and insulin enhancing potential in vivo or is to be regarded as an independent pharmacological effect.     

The National Cancer Data Base report on Hodgkin''s disease for 1985-1989 and 1990-1994

OBJECTIVE: Terbutaline, a selective beta2-agonist, is a frequently used tocolytic known to affect maternal metabolism. The purpose of this study was to evaluate the effect of oral terbutaline on maternal glucose metabolism and energy expenditure. STUDY DESIGN: Six healthy pregnant women with normal glucose tolerance were evaluated between 30 and 34 weeks' gestation. Oral terbutaline was administered to determine the effects on hepatic glucose production with [6-6(2)H2] glucose tracer, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and energy expenditure (indirect calorimetry). Terbutaline, insulin, and glucagon levels were also obtained. Subjects were randomly assigned to either oral terbutaline 5 mg every 6 hours for 24 hours or no medication. Repeat studies were conducted 1 week apart, each subject serving as her own control. RESULTS: In the basal state terbutaline was associated with a trend toward increased basal glucose levels (81.6 +/- 6.6 vs 93.7 +/- 12.0 mg/dl, p = 0.06) but no significant increase in hepatic glucose production (3.2 +/- 0.3 vs 3.6 +/- 0.4 mg/kg fat-free mass/min, p = 0.23). However, there was a significant increase in basal insulin concentration (17.6 +/- 9.2 vs 25.6 +/- 10.4 microU/ml, p = 0.02). There was a 28% decrease in insulin sensitivity as measured by the glucose infusion rate during the euglycemic clamp plus residual hepatic glucose turnover (5.78 +/- 1.91 vs 4.16 +/- 1.49 mg/kg fat-free mass/min, p = 0.005). Glucagon concentration was significantly decreased both in the basal state (163 +/- 26 vs 144 +/- 27 pg/ml, p = 0.0007) and during the clamp (144 +/- 27 vs 133 +/- 27 pg/ml, p = 0.003). Basal oxygen consumption increased 9% (270 +/- 49 vs 294 +/- 50 ml oxygen/min, p = 0.007) and caloric expenditure 14% (1.32 +/- 0.23 vs 1.50 +/- 0.31 kcal/min, p = 0.025) or 260 kcal/day with terbutaline. CONCLUSION: Decreased peripheral insulin sensitivity, and to a lesser degree increased endogenous glucose production, may represent the pathophysiology of abnormal glucose tolerance observed in many women treated with oral terbutaline. Common side effects such as tremors and tachycardia experienced by many women on a regimen of terbutaline are consistent with our finding of a significant increase in basal energy expenditure.