Plasma glycohydrolase levels in patients with type 1 diabetes at onset and in subjects undergoing an intravenous glucose tolerance test

The effect of hyperglycemia and insulin deficiency on the plasma level of lysosomal glycohydrolases, namely N-acetyl-beta-D-glucosaminidase, beta-D-glucuronidase, alpha-D-galactosidase, and alpha-D-glucosidase, was investigated. Two patient groups were assessed: (1) 28 children with type 1 diabetes at onset (fasting blood glucose, 444+/-154 mg/100 mL; hemoglobin A1c, 11.9%+/-2.4%; symptom duration, 15.9+/-8 days; and absence of complications), (2) 14 adult subjects undergoing an intravenous glucose tolerance test (IVGTT), consisting of 8 non-obese subjects (body mass index, 26+/-0.04 kg/m2; fasting blood glucose, 82+/-13 mg/100 mL; blood insulin, 6+/-0.04 mU/L) and 6 obese subjects (fasting blood glucose, 97+/-3.5 mg/100 mL; blood insulin, 27+/-6 mU/L, with normal oral glucose tolerance test). Enzyme activity was determined with the fluorimetric method. The mean level of all evaluated enzymes was significantly increased in patients with type 1 diabetes at diagnosis compared with normal controls. Increased enzyme levels were also detected in the group of adults undergoing an IVGTT in whom hyperglycemia was accompanied by insulin resistance (ie, obese subjects). Glycohydrolase abnormalities appear to be related to insulin deficiency rather than hyperglycemia. Lysosomal apparatus abnormalities seem to be an inherent feature of diabetes that is present at disease onset. The possible role of insulin in the regulation of plasma glycohydrolase levels is discussed.     

The effect of epinephrine on glucose-mediated and insulin-mediated glucose disposal in insulin-dependent diabetes.

The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mU/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGTT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 +/- 0.3 SE v 7.7 +/- 0.7 mmol/L, P less than .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 +/- 0.1 v 0.3 +/- 0.1 mmol/L, P less than .05); and (3) profoundly reduced glucose disposal (KG 0.59 +/- 0.1 v 1.91 +/- 0.33 min-1 x 10(2), P less than .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 +/- 0.5 v CTR 7.03 +/- 3.2 min-1.mU-1.L x 10(4), P less than .05) with no significant change in SG (EPI 2.5 +/- 0.2 v CTR 3.1 +/- 0.5 min-1 x 10(2), NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

B cell secretion and insulin sensitivity in hypertensive and normotensive obese subjects

To test the hypothesis that in obesity hypertension is associated with more pronounced hyperinsulinaemia and insulin resistance we compared plasma insulin levels and insulin sensitivity in a group of 6 obese subjects with untreated hypertension and in a group of 6 obese subjects with normal blood pressure. The two groups were similar for sex, age, body mass index and glucose tolerance. Six nonobese subjects served as controls. The study consisted of a 2-h hyperglycaemic clamp (steady-state plasma glucose = 11 mmol/l) and a 15-min insulin tolerance test (0.1 U/kg body wt). During hyperglycaemic clamp, insulin and C-peptide plasma levels were similar in normotensive and hypertensive obese subjects: the area under the plasma insulin curve was 36,000 +/- 3000 pmol/l X 120 min in the former and 34,000 +/- 1000 pmol/l X 120 min in the latter; the area under the plasma C-peptide curve was 298,000 +/- 26,000 pmol/l X 120 min in the former and 246,000 +/- 26,000 pmol/l X 120 min in the latter (P = n.s.). The ratio M/I between the amount of glucose metabolized (M) and the mean plasma insulin levels (I) during hyperglycaemic clamp was similar in the two groups: 0.59 +/- 0.09 in normotensive and 0.58 +/- 0.08 mg/min X m2 per pmol/l in hypertensive obese subjects (P = n.s.). Also the rate coefficient of glucose disappearance from plasma (K(itt)) after i.v. insulin injection was similar in the two groups (4.08 +/- 0.51 vs. 3.87 +/- 0.53 per cent/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effect of weight loss on insulin resistance in surgically treated obese patients

PURPOSE: To compare the effects of equivalent weight loss induced by two bariatric surgical techniques on insulin action in severely obese patients. METHODS: Eighteen nondiabetic patients with severe obesity (mean [+/- SD] body mass index: 53.5 +/- 9.0 kg/m(2)) and 20 sex- and age-matched lean subjects (body mass index: 23.8 +/- 3.0 kg/m(2)) underwent metabolic studies, including measurement of insulin sensitivity by the insulin clamp technique. Patients then underwent either vertical banded gastroplasty with Roux-en-Y gastric bypass, or biliopancreatic diversion, and were restudied at 5 to 6 months and again at 16 to 24 months postsurgery. RESULTS: At baseline, patients were hyperinsulinemic (194 +/- 47 pmol/L vs. 55 +/- 25 pmol/L, P < 0.0001), hypertriglyceridemic (1.56 +/- 0.30 mmol/L vs. 0.78 +/- 0.32 mmol/L, P < 0.0001), and profoundly insulin resistant (insulin-mediated glucose disposal: 20.8 +/- 4.4 micromol/min/kg fat-free mass vs. 52.0 +/- 10.1 micromol/min/kg, P < 0.0001) as compared with controls. Weight loss by the two procedures was equivalent in both amount (averaging -53 kg) and time course. In the gastric bypass group, insulin sensitivity improved (23.8 +/- 6.0 micromol/min/kg at 5 months and 33.7 +/- 11.3 micromol/min/kg at 16 months, P < 0.01 vs. baseline and controls). In contrast, in the biliopancreatic diversion group, insulin sensitivity was normalized already at 6 months (52.5 +/- 12.4 micromol/min/kg, P = 0.72 vs. controls) and increased further at 24 months (68.7 +/- 9.5 micromol/min/kg, P < 0.01 vs. controls) despite a persistent obese phenotype (body mass index: 33.2 +/- 8.0 kg/m(2)). CONCLUSION: In surgically treated obese patients, insulin sensitivity improves in proportion to weight loss with use of predominantly restrictive procedures (gastric bypass), but is reversed completely by predominantly malabsorptive approaches (biliopancreatic diversion) long before normalization of body weight. Selective nutrient absorption and gut hormones may interact with one another in the genesis of the metabolic abnormalities of obesity.     

Evidence that glucose transport is rate-limiting for in vivo glucose uptake.

To determine whether glucose transport or intracellular glucose metabolism is rate-limiting for in vivo glucose uptake, rates of glucose disposal were measured in a group of normal subjects at varying levels of hyperglycemia designed to attain saturating rates of glucose disposal at low and high physiological insulin concentrations. At insulin levels of approximately 200 pmol/L, glucose disposal rates were 2.9 +/- 0.4, 4.7 +/- 0.5, 6.4 +/- 0.6, and 6.5 +/- 0.8 mg/kg/min at plasma glucose concentrations of 5.55, 11.10, 13.88, and 19.43 mmol/L (or 100, 200, 250, and 350 mg/dL, respectively). At insulin levels of approximately 750 pmol/L, glucose disposal rates were 1.7 to 2.1-fold higher: 6.2 +/- 0.7, 9.2 +/- 1.1, 11.0 +/- 1.1, and 12.3 +/- 1.4 mg/kg/min at glucose levels of 5.55, 11.10, 13.88, and 19.43 mmol/L. Thus, during both the 15- and 40-mU/m2/min insulin infusions, glucose disposal increased in a linear fashion from 5.55 to 13.88 mmol/L (r = .90) and then effectively plateaued at the same plasma glucose level. If the plateau of glucose disposal during the 40-mU/m2/min insulin infusion was due to saturation of the intracellular capacity to metabolize glucose, then when plasma glucose was increased from 13.88 to 19.43 mmol/L at the lower insulin level, the glucose disposal should have continued to increase and not plateau, since the rate of glucose disposal was only approximately 50% of that attained at the higher insulin infusion rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Somatostatin enhances insulin-mediated glucose disposal in elderly subjects

Somatostatin (SRIH) infusion has been widely used in metabolic studies of carbohydrate metabolism. While the effects of SRIH itself on various aspects of carbohydrate economy have been assessed in young adults, such studies have not been conducted in the elderly, which represent an increasingly important study group. To examine the effect of SRIH on insulin-mediated glucose disposal in the elderly, we studied 12 (7 men and 5 women) healthy nonobese subjects, aged 65-80 yr. Paired 3-h euglycemic insulin clamp studies were performed in random order employing insulin alone (22 mU/m2.min) or insulin with SRIH (250 micrograms/h) and glucagon (0.4 ng/kg.min) to maintain normal basal plasma glucagon levels. Basal plasma insulin, glucose, glucagon, GH, and glucose production and disappearance were similar on each occasion. Steady state (10-180 min) mean plasma insulin [insulin alone, 298 +/- 12 (+/- SE); insulin; glucagon, and SRIH, 304 +/- 15 pmol/L] and glucagon (insulin alone, 85 +/- 7; insulin, glucagon, and SRIH, 96 +/- 9 ng/L) concentrations were similar. At steady state (150-180 min) glucose production was suppressed to similar levels (insulin alone, 26 +/- 7; insulin, glucagon, and SRIH, 36 +/- 13 mumol/kg.min). However, steady state glucose disposal was significantly higher during the SRIH infusion (insulin alone, 295 +/- 26; insulin, glucagon, and SRIH, 346 +/- 32 mumol/kg.min; P less than 0.02). We conclude that SRIH augments insulin-mediated glucose disposal in healthy older subjects at physiological levels of insulin.     

Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy

Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/- 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass index. Moreover, after metformin therapy, hyperandrogenemia and hyperinsulinemia were normalized, and glucose utilization improved [obese before: total T, 0.9 +/- 0.15 ng/ml; fasting insulin, 22.2 +/- 12.1 U/liter; glucose utilization, 2.15 +/- 0.5 mg/kg.min; obese after: total T, 0.5 +/- 0.2 ng/ml; fasting insulin, 11.6 +/- 6 U/liter; glucose utilization, 4.7 +/- 1.4 mg/kg.min 9P < 0.003, P < 0.006, and P < 0.002, respectively); nonobese before: total T, 1 +/- 0.5 ng/ml; fasting insulin, 15.5 +/- 7.6 U/liter; glucose utilization, 3.4 +/- 0.7 mg/kg.min; nonobese after: total T, 0.8 +/- 0.5 ng/ml; fasting insulin, 9 +/- 3.8 U/liter; glucose utilization, 6 +/- 1.7 mg/kg.min (P < 0.04, P < 0.02, and P < 0.0008, respectively)]. In conclusion, our data clearly demonstrate that women with polycystic ovary syndrome, obese and nonobese, have elevated endothelin-1 levels compared with the age-matched control group. In addition, 6 months of metformin therapy reduces endothelin-1 levels and improves their hormonal and metabolic profile.     

Intracellular partition of plasma glucose disposal in hypertensive and normotensive subjects with type 2 diabetes mellitus

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.     

A low-carbohydrate/high-fat diet improves glucoregulation in type 2 diabetes mellitus by reducing postabsorptive glycogenolysis

The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 +/- 11 and 123 +/- 11 mg/dl (8.2 +/- 0.6 and 6.8 +/- 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 +/- 2 and 10 +/- 1 microIU/ml (82 +/- 11 and 66 +/- 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 +/- 0.06 vs. 1.55 +/- 0.05 mg/kg.min (10.44 +/- 0.33 vs. 8.61 +/- 0.28 micromol/kg.min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.     

Effect of obesity on susceptibility to fatty acid-induced peripheral tissue insulin resistance

Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown to impair the actions of insulin on peripheral glucose uptake and suppression of hepatic glucose output (HGO). These studies have been conducted almost exclusively in healthy, lean men. We therefore set out to test the hypothesis that obese subjects, because they are already insulin-resistant, are less susceptible than lean subjects to the inhibitory effects of elevated NEFA on insulin-stimulated glucose disposal. We studied 15 lean (11 men, 4 women; age, 45 +/- 3 years [mean +/- SE]; body mass index [BMI], 22.7 +/- 0.6 kg/m(2)) and 15 obese normal subjects (11 men, 4 women; 49 +/- 3 years; 31.7 +/- 1.0 kg/m(2)). Each subject underwent two 5-hour 80-mU/m(2)/min hyperinsulinemic euglycemic clamps with measurement of glucose kinetics (intravenous 3-(3)H-glucose). Plasma NEFA levels were elevated in one study for 3 hours before and during the clamp ( approximately 1 mmol/L in both groups) by infusion of 20% Intralipid (60 mL/h) and heparin (900 U/h). The obese subjects had higher fasting insulin levels (9.1 +/- 1.1 v 4.8 +/- 0.6 mU/L, P <.005) and were insulin-resistant (glucose disposal rate [GDR] at the end of the control glucose clamps: obese, 7.96 +/- 0.55, lean, 10.24 +/- 0.35 mg/kg/min, P <.002). Contrary to our hypothesis, elevation of plasma NEFA had a similar effect in the lean and obese subjects, both in terms of the absolute reduction of insulin stimulated GDR in the lean (1.82 +/- 0.36 mg/kg/min decrement) and obese subjects (2.03 +/- 0.37 mg/kg/min decrement) and the overall percentage reduction in GDR (lean, 17.1% +/- 3.1%; obese, 24.5% +/- 4.2%; difference not significant [NS]). Suppression of HGO during the lipid clamps was also impaired to a similar extent in the 2 groups. Findings were similar for the 9 obese subjects with a BMI of 30 kg/m(2) or more. Combining the 2 groups, the NEFA induced reduction of insulin stimulated GDR did not correlate with BMI (r = 0.08, NS) or with insulin sensitivity (GDR) measured in the control study (r = 0.11, NS). In summary, the effect of a short term elevation of plasma NEFA levels on insulin stimulated GDR and suppression of HGO is comparable in lean and moderately obese subjects.     

Fuel metabolism in anorexia nervosa and simple obesity

To examine insulin sensitivity and the relative contribution of different fuels to energy metabolism in anorexia nervosa and obesity, we measured oxidation (indirect calorimetry) of glucose, lipids, and proteins in the basal state and during an insulin clamp (+45 mU/m2.min) in 11 women with anorexia nervosa (age, 25 +/- 3 years; body mass index [BMI], 13.6 +/- 0.4 kg/m2; fat mass, 15.7% +/- 1.6%), eight obese women (age, 31 +/- 3; BMI 36.0 +/- 1.5; fat mass, 47.1% +/- 1.9%), and eight controls (age, 26 +/- 3; BMI, 21.8 +/- 0.9; fat mass, 25.7% +/- 3.6%). Expressed per lean body mass, (LBM), glucose disposal was equally reduced in anorectics (7.53 +/- 0.62 mg/kg LBM.min) and obese (6.80 +/- 1.07 mg/kg LBM.min) compared with controls (10.64 +/- 0.69 mg/kg LBM.min; P less than .01). The reduction in glucose disposal in anorectics was primarily due to a significant (P less than .01) reduction in glucose storage, while glucose oxidation was normal. In obese women, both storage and oxidation of glucose were reduced compared with controls (P less than .01). Basal energy expenditure was similar in anorectic, obese, and control subjects (20.6 +/- 1.00, 23.7 +/- 0.56, 23.2 +/- 1.36 cal/kg LBM.min, respectively). However, the contribution of glucose, lipids, and proteins to basal energy expenditure differed between anorectic (62%, 16%, 22%), obese (26%, 58%, 16%), and control (30%, 54%, 16%) subjects (P less than .05 v all). In conclusion, in anorexia nervosa, insulin stimulates glucose oxidation more than storage. In obesity, both components of insulin-stimulated glucose metabolism are impaired.(ABSTRACT TRUNCATED AT 250 WORDS)     

Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects

OBJECTIVE: Platelet aggregation responses to acetylsalicylic acid (ASA) show considerable interindividual variation, the causes of which are largely unknown. We determined whether variation in insulin action is associated with that of ASA on platelets. SUBJECTS: In all, 10 nonobese (age 50+/-3 y, BMI 25+/-1 kg/m(2)) and 11 obese (age 52+/-2 y, BMI 32+/-1 kg/m(2)) subjects. MEASUREMENTS: Insulin sensitivity of glucose uptake was determined by the euglycemic insulin clamp technique. Platelet aggregation responses to four doses of arachidonic acid (AA) and adenosine diphosphate (ADP) were assessed in platelet-rich plasma before and 1 h after ingestion of 50 mg ASA using Born's turbidometric aggregometer. RESULTS: Whole-body insulin sensitivity (M-value 0-180 min) was 36% lower in the obese (4.5+/-0.6) than the nonobese (7.1+/-0.6 mg/kg min, P<0.01) group. Before ASA, all doses of AA induced complete aggregation. After ASA ingestion, ASA inhibited maximal aggregation more in the nonobese than the obese group at AA concentrations of 0.75, 1 and 1.5 mmol/l (P=0.016 for ANOVA). ADP-induced aggregation at high doses (2 and 3 micromol/l) was also less inhibited in the obese group. In vivo insulin sensitivity (r=-0.68, P<0.001 for 1 mmol/l AA) and BMI (r=0.58, P<0.01 for 1 mmol/l AA) were closely correlated with residual aggregation after ASA administration. CONCLUSION: These data demonstrate that obese insulin-resistant subjects have a blunted response to platelet-inhibitory effect of ASA. If this blunted effect is of a single dose of ASA preserved in continuous use, it could contribute to the increased risk of atherothrombosis in insulin-resistant individuals.     

Relationships of obesity indices to serum insulin and lipoproteins in relatives of black patients with noninsulin-dependent diabetes mellitus (NIDDM)

We have examined the relationships between obesity indices and various metabolic parameters in seven obese (body mass index (BMI) mean +/- s.e.m. 42 +/- 2.5 kg/m2), ten nonobese (BMI 25.3 +/- 1.2 kg/m2) nondiabetic female relatives of black patients with NIDDM and eight healthy controls (BMI 24.5 +/- 1.1 kg/m2). Despite the greater BMI in the obese relatives, percent body fat was not different from that of the nonobese relatives (38 +/- 2 vs 34 +/- 3 percent). Both values were, however, significantly (P less than 0.05) greater than that of the healthy controls (25 +/- 3 percent). Mean waist-to-hip circumference ratio (WHR) was greatest in obese relatives (0.89 +/- 0.01), intermediate in nonobese relatives (0.83 +/- 0.01) and least in the healthy controls (0.77 +/- 0.04). Mean sum of skinfold thickness from biceps, triceps and subscapular (SS) region was also greatest in obese relatives, intermediate in nonobese relatives and least in controls. Centrality index was not, however, different among the groups. Mean fasting serum glucose levels were slightly higher but not significantly different in the relatives compared to controls (obese 82 +/- 3; nonobese 81 +/- 4; controls 75 +/- 3 mg/dl). Following oral glucose ingestion, serum glucose rose to significantly (P less than 0.05) greater levels at 30, 60 and 90 min in the relative subgroups vs controls. Mean fasting and post-prandial peak serum insulin concentrations were significantly (P less than 0.05-0.01) greater in both relative subgroups vs controls. While mean serum glucose profiles and glucose disappearance decay (KG) following intravenous glucose load were identical in the relatives and controls, serum insulin responses were significantly greater in the relatives. The mean basal and post-stimulation serum C-peptide concentrations were similar in all the three groups, irrespective of the stimulus; thus suggesting a reduced hepatic insulin extraction in the relatives. Fasting serum cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) as well as FFA levels were not different between the relatives and controls despite the hyperinsulinemia in the former group. WHR correlated with basal insulin in the relatives (r = 0.416, P less than 0.05) and controls (r = 0.68, P less than 0.01) but not with stimulated insulin, lipids and lipoproteins in any of the groups. In contrast, both percent BFM and SS thickness correlated significantly (P less than 0.001) with post-glucose insulin concentrations in the relatives only.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cholinergic blockade with pirenzepine induces dose-related reduction in glucose and insulin responses to a mixed meal in normal subjects and non-insulin dependent diabetics

OBJECTIVE: The aim of the study was to assess the effects of cholinergic blockade with pirenzepine on glucose and insulin responses to a mixed meal in normal subjects and patients with non-insulin dependent diabetes (NIDDM). Further, to assess in normal subjects the relative importance of nocturnal GH suppression by pirenzepine. DESIGN: Placebo, 100 or 200 mg pirenzepine were given to the normal subjects 1 hour before a standard mixed meal. The effects of placebo or 200 mg pirenzepine at night on nocturnal GH secretion and subsequent breakfast carbohydrate tolerance were also studied. NIDDMs were given placebo or 200 mg pirenzepine before the meal. SUBJECTS: We studied six healthy male volunteers (ages 20-22, body mass indices 20.3-23.3) and ten NIDDMs (eight men, ages 42-74); five obese (BMI 25.5-31.8) and five non-obese (BMI 21.2-24.8). MEASUREMENTS: Serial plasma glucose and insulin concentrations were measured for 3 hours after a standard mixed meal. RESULTS: Acute pretreatment of normal male volunteers with pirenzepine produced a dose-related improvement in carbohydrate tolerance. Peak post-prandial plasma glucose levels were delayed and significantly reduced following 200 mg orally (6.5 +/- 0.1 mmol/l), but not following 100 mg (7.3 +/- 0.3), compared with placebo (7.6 +/- 0.3). Peak insulin levels were similarly delayed and reduced by the 200 mg dose only (36.5 +/- 6.1 mU/l, compared with 49.8 +/- 8.7). Suppression of nocturnal GH by 200 mg pirenzepine at night produced a small reduction in fasting plasma glucose (5.0 +/- 0.1 mmol/l, compared with 5.3 +/- 0.1, P less than 0.02) but did not improve subsequent breakfast carbohydrate tolerance. Peak plasma glucose in NIDDMs was reduced following pirenzepine (12.4 +/- 0.9 mmol/l) compared with placebo (14.3 +/- 1.0, P less than 0.01). This reduction was equally significant in obese and non-obese groups. Peak plasma insulin was also reduced by pirenzepine (22.4 +/- 3.9 mU/l) compared with placebo (42.4 +/- 5.3, P less than 0.01). Insulin suppression was quantitatively greater in obese than in non-obese patients. CONCLUSIONS: Improvement in carbohydrate tolerance after pirenzepine in normal subjects is dose related and largely independent of GH suppression. Cholinergic blockade can also improve meal carbohydrate tolerance with simultaneous reduction in plasma insulin concentrations in non-insulin dependent diabetics, particularly those with obesity.     

Effect of short-term consumption of a high-fat, low-carbohydrate diet on metabolic control in insulin-deficient diabetic rats

This study examined the effect of changing the proportion of dietary fat on metabolic control in rats rendered mildly diabetic with streptozotocin (STZ). The high-fat (HF) diet contained 66% energy as fat and 12% as carbohydrate while the low-fat (LF) diet contained 12% energy as fat and 66% as carbohydrate. Both diets had a P/S ratio of 1:3. Young male rats weighing 100 g were treated with STZ (60 mg/kg IV) and randomly allocated to either the LF of HF diet. After 2 weeks, the fasting plasma glucose concentrations were significantly higher in the HF-STZ rats than in the LF-STZ rats (13.2 +/- 1.2 mmol/L v 7.1 +/- 0.8 mmol/L, respectively, P less than 0.001). The increase in plasma glucose above the basal level following the intravenous glucose load (0.5 g/kg body wt) was similar in both groups of STZ-treated rats and glucose clearance was similarly impaired. The fall in glucose concentrations in the 30 minutes following the IV insulin (0.5 U Actrapid insulin/kg body wt) was greater in the LF-STZ rats (delta AUC = -1.60 +/- 0.20 mmol/L 0.5h) than in the HF-STZ group (delta AUC = -0.97 +/- 0.20 mmol/L 0.5 h, P less than 0.05) and either of the control groups (delta AUC = -0.94 +/- 0.37, -0.83 +/- 0.09 mmol/L 0.5 h for LF and HF rats, respectively, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of impaired intracellular glucose metabolism in the insulin resistance of aging.

The insulin resistance of aging is characterized by both reduced glucose uptake and impaired intracellular glucose metabolism. The aim of this study was to determine whether impaired intracellular glucose metabolism contributes to insulin resistance in the elderly independent of reduced glucose uptake. To address this question, glucose uptake in non-obese elderly males was matched to controls using the glucose clamp technique, and intracellular glucose metabolism was assessed in vivo by indirect calorimetry and in vitro by skeletal muscle biopsy for glycogen synthase activity. When elderly subjects were compared with controls at an equivalent basal glucose uptake of approximately 2.5 mg/kg fat-free mass (FFM)/min, muscle glycogen synthase activity was similar (fractional velocity of glycogen synthase at 0.1 mmol/L glucose-6-phosphate [FV0.1], 0.06 +/- 0.1 and 0.07 +/- 0.1), but whole-body rates of glucose oxidation were reduced (1.36 +/- 0.12 v 1.90 +/- 0.11 mg/kg FFM/min, P less than .05). During 40-mU/m2/min hyperinsulinemic clamps at matched rates of glucose uptake (approximately 10.7 mg/kg FFM/min in both groups), glycogen synthase activity was again similar (FV0.1, 0.15 +/- 0.02 and 0.14 +/- 0.02), and glucose oxidation remained reduced in the elderly (4.18 +/- 0.25 v 4.77 +/- 0.17 mg/kg FFM/min, P less than .05). Only during clamps in the maximal range of glucose uptake (approximately 29.5 mg/kg FFM/min) was glucose oxidation between the groups comparable (5.97 +/- 0.50 and 5.75 +/- 0.31 mg/kg FFM/min). Plasma free fatty acid (FFA) concentrations, fat oxidation, and protein oxidation were similar under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and renal sodium retention in obese adolescents

The effect of insulin on the renal handling of sodium was studied in obese and nonobese subjects by using euglycemic hyperinsulinemia. Seven water-loaded obese (14-19 years old) and five nonobese young adults (18-21 years old) had insulin given intravenously at a rate of 40 munits/m2/min. Blood glucose and creatinine clearance were not altered by euglycemic hyperinsulinemia in either the obese or the nonobese group. Hyperinsulinemia resulted in a significant decrease in urinary sodium excretion in both groups of subjects (by 54.2 +/- 3% [mean +/- SEM] in the obese and by 50.9 +/- 3.1% in the nonobese group). However, the amount of glucose required to maintain euglycemia was significantly less in the obese versus nonobese group, 89.5 +/- 6.2 versus 329.2 +/- 16 mg glucose/m2/min (p less than 0.001). There was no relation in either group between the amount of glucose required to maintain euglycemia and the change in urinary sodium excretion. On a separate day, all of the obese subjects underwent 3 hours of water diuresis but without insulin. There was no change in urinary sodium excretion with sustained water diuresis alone. However, when compared with the nonobese group, the obese group of subjects had a significantly higher resting mean arterial pressure, heart rate, and plasma norepinephrine concentration; during the insulin clamp, neither group experienced a significant change in mean arterial pressure or heart rate, and only the nonobese group experienced an increase in plasma norepinephrine. In obese subjects, we have found, despite the presence of insulin resistance to carbohydrate metabolism, that euglycemic hyperinsulinemia was associated with a normal decrease in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired glucose metabolism in surgical patients improved by intravenous nutrition: assessment by the euglycemic-hyperinsulinemic clamp

Malnutrition is associated with glucose intolerance. This could be related to decreased pancreatic insulin secretion and/or peripheral insulin resistance. We have used the euglycemic-hyperinsulinemic clamp and continuous indirect calorimetry to assess the disposal of an intravenous glucose load in 13 malnourished patients with benign disease (median age, 55 years; mean weight loss 21 kg +/- 8 SD). Seven normally nourished controls were also studied (median age, 62 years) and eight patients were restudied after 14 days on continuous glucose-based intravenous nutrition (IVN). With hyperinsulinemia of 90 microU/mL, malnourished patients disposed of 6.1 mg glucose/kg fat-free body (FFB).min +/- 1.7 SD and oxidized 1.9 mg/kg FFB.min +/- 1.4 SD. Controls disposed of a similar amount of glucose (6.6 mg/kg FFB.min +/- 3.5 SD) but oxidized significantly more (3.0 mg/kg FFB.min +/- 2.3 SD). After two weeks of glucose-based IVN, both glucose disposal rate (9.5 mg/kg FFB.min + 2.3 SD) and oxidation rate (3.9 mg/kg FFB min +/- 1.0 SD) increased significantly. Respiratory quotient was low in malnourished patients (.88 +/- .12), but above 1.0 in controls (1.07 +/- 0.18) and patients after IVN (1.10 +/- 0.11), showing net lipogenesis in these groups. Malnourished patients can metabolize normal amounts of glucose under conditions of hyperinsulinemia and, although carbohydrate oxidation rate is initially impaired, it becomes normal after 2 weeks of IVN.     

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.     

Insulin sensitivity in physically fit and unfit children of parents with Type 2 diabetes.

AIMS: First-degree relatives of patients with Type 2 diabetes mellitus (T2DM) are often reported to be insulin resistant. We wanted to identify early metabolic abnormalities in this condition, and determine whether they are altered by regular physical training. METHODS: We measured insulin sensitivity using the euglycaemic glucose clamp technique and insulin response to oral glucose in 10 unfit (did not participate in routine physical exercise) offspring of T2DM parents and 10 unfit control subjects, and compared them with six fit (routinely swam for 3 h/day 5 days/week) offspring of T2DM parents and six fit controls with no family history of T2DM. RESULTS: Unfit offspring had a higher plasma glucose response than the other three groups. The mean area under the glucose curve was also significantly higher in unfit offspring than in the other three groups (12.6 +/- 0.6 vs. 10.4 +/- 0.4, 9.6 +/- 0.5, and 9.5 +/- 0.7 mmol/l per hour for the unfit controls, fit offspring and fit controls, respectively; P < 0.05). The corresponding insulin response of unfit offspring was significantly higher at 60 min in the oral glucose tolerance test (OGTT) that that of fit offspring or fit controls. In addition, the mean area under the insulin curve was significantly greater in unfit offspring than in either fit offspring or fit controls (868 +/- 172 vs. 294 +/- 71, 287 +/- 43 mmol/l per hour, respectively; P < 0.05). Moreover, the glucose disposal rate (GDR), measured using a euglycaemic clamp, was significantly lower in unfit and fit offspring than in unfit and fit controls (5.6 +/- 0.3 vs. 8.6 +/- 0.3 mg/kg per minute; P < 0.01 and 9.3 +/- 0.9 vs. 12.1 +/- 0.8 mg/kg per minute, respectively; P < 0.015), whereas the GDR was similar in unfit controls and fit offspring (8.6 +/- 0.4 vs. 9.3 +/- 0.9 mg/kg per minute; P > 0.05). CONCLUSION: These results support the concept that early metabolic abnormalities, as reflected by a decreased GDR (insulin sensitivity) in the offspring of T2DM patients, may be improved by increased physical fitness.