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

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

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

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

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

HYPERINSULINAEMIA AND INSULIN RESISTANCE OF CIRRHOSIS: THE IMPORTANCE OF INSULIN HYPERSECRETION

The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and C-peptide plasma levels in patients with severe chronic pancreatitis and fasting normoglycemia

The aim of the present study was to evaluate insulin secretion by the pancreatic B cell in a group of patients with severe chronic pancreatitis and without overt diabetes. For this purpose we have measured plasma insulin and C-peptide peripheral levels in the fasting state and after a 100-g oral glucose load in 10 patients with severe chronic pancreatitis and fasting normoglycemia, and in 10 sex-, age-, and weight-matched healthy controls. As compared to normal subjects, patients with chronic pancreatitis showed: (1) significantly higher plasma glucose levels after oral glucose load (area under the plasma glucose curve 1708 +/- 142 vs 1208 +/- 47 mmol/liter X 240 min, P less than 0.005); (2) plasma insulin levels significantly higher at fasting (0.11 +/- 0.008 vs 0.08 +/- 0.005 nmol/liter, P less than 0.01) but not after oral glucose administration (area under the plasma insulin curve 79 +/- 12 vs 88 +/- 16 nmol/liter X 240 min); (3) significantly lower plasma C-peptide concentrations both in the fasting state (0.15 +/- 0.01 vs 0.54 +/- 0.05 nmol/liter, P less than 0.001) and after oral glucose load (area under the plasma C-peptide curve 211 +/- 30 vs 325 +/- 37 nmol/liter X 240 min, P less than 0.05). The finding of diminished plasma C-peptide levels suggests that chronic pancreatitis is associated with an impaired B-cell function even in the absence of overt diabetes. The increased or unchanged plasma insulin levels in spite of decreased plasma C-peptide concentrations indicate that in chronic pancreatitis insulin metabolism is reduced, most likely within the liver.     

Peripheral and hepatic insulin antagonism in hyperthyroidism

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.     

Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type 1 diabetes

The influence of continuous sc insulin infusion therapy for 6 weeks on sensitivity to insulin (euglycemic clamp technique) and hepatic glucose production (3-[3H]glucose technique) was measured in 10 type 1 diabetic patients whose mean duration of diabetes was 8 yr. Mean diurnal blood glucose fell from 8.5 +/- 0.8 (SEM) mmol/liter to 6.0 +/- 0.6 mmol/liter (P less than 0.05) and glycosylated hemoglobin from 10.5 +/- 0.4% to 8.7 +/- 0.3%. Insulin requirements declined by 23% from 47 +/- 4 U/day prepump to 36 +/- 2 U/day after 6 weeks of pump therapy (P less than 0.01). During the insulin clamp, plasma insulin was maintained at approximately 90 mU/liter and plasma glucose at approximately 5.0 mmol/liter in all studies. The rate of glucose metabolism in diabetic patients during conventional therapy (4.65 +/- 0.41 mg/kg X min) was 35% lower than in normal subjects (7.20 +/- 0.42 mg/kg X min, n = 14, P less than 0.001). After 6 weeks of pump therapy, total glucose uptake increased by 27% to 5.90 +/- 0.60 mg/kg X min, P less than 0.05 vs. prepump). This was still 18% lower than in the normal subjects (P less than 0.05). Basal hepatic glucose production in the diabetic patients during conventional therapy (3.07 +/- 0.14 mg/kg X min) was 70% higher than in the normal subjects (1.79 +/- 0.07 mg/kg X min, n = 7, P less than 0.001). After 6 weeks of pump therapy, hepatic glucose production fell to 2.48 +/- 0.19 mg/kg X min (P less than 0.05), which was still 40% higher than in the normal subjects (P less than 0.01). Basal hepatic glucose production was directly related to the fasting plasma glucose level (r = 0.67, P less than 0.001) and inversely proportional to fasting insulin concentration (r = -0.48, P less than 0.05) in the diabetic patients. Specific tracer insulin binding to erythrocytes in the diabetic patients (19.4 +/- 1.5%) was comparable to that in the normal subjects (19.6 +/- 1.2%) and remained unchanged during pump therapy. Thus the improved metabolic control resulting from pump therapy is associated with enhancement in sensitivity to insulin, and reduction in basal hepatic glucose production.     

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients.

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.     

Insulin antagonism is not a primary abnormality of amyotrophic lateral sclerois but is related to disease severity

Sensitivity to insulin was studied in 13 patients with amyotrophic lateral sclerosis (ALS) and 10 age- and weight-matched normal subjects by performing euglycemic clamp studies at low (1.5 mU/kg X min) and high (10 mU/kg X min) insulin infusion rates. Mean glucose disposal rates were similar in the ALS patients and normal subjects at both the low [4.8 +/- 0.6 (+/- SEM) vs. 5.2 +/- 0.6 mg/kg X min] and high (9.2 +/- 1.3 vs. 9.8 +/- 0.5 mg/kg X min) insulin infusion rates, respectively. Binding of [125I] iodoinsulin to monocytes was also similar in seven patients with ALS (3.8 +/- 1.0%/10(7) cells) and 10 normal subjects (3.9 +/- 0.9). However, glucose disposal rates correlated inversely with disease severity in the ALS patients, at both the low (r = -0.76; P less than 0.01) and high (r = -0.83; P less than 0.001) insulin infusion rates. We conclude that insulin antagonism is not a primary abnormality of ALS, but may be related to the inactivity associated with disease progression.     

Correlation between insulin clearance and insulin responsiveness: studies in normal, obese, hyperthyroid, and Cushing's syndrome patients

Insulin clearance and secretion determine the plasma insulin concentration. To elucidate the significance of these parameters in man, we employed the euglycemic insulin clamp technique to measure insulin sensitivity, insulin responsiveness, and insulin clearance, and we calculated the basal insulin delivery rate. In 27 patients (six normal, six obese, ten hyperthyroid, and five with Cushing's syndrome), insulin was infused at rates of 0.3, 1, 3, or 10 mU/Kg/min, and insulin concentration and glucose utilization were measured. C-peptide concentrations were measured before and during insulin infusion and decreased significantly, indicating a reduction of endogenous insulin secretion to 62% of basal in normals and a similar reduction in the other groups. Maximal responsiveness to insulin was a glucose utilization rate of 450 +/- 20 mg/min/m2 in normals, unchanged in obese, 42% increased in hyperthyroid, and 34% decreased in Cushing's syndrome patients. Sensitivity to insulin was decreased in all three abnormal groups. Insulin clearance rates were 1,050 +/- 80 mL/min/m2 for normals, not significantly changed in obese, 45% increased in hyperthyroid, and 33% decreased in Cushing's syndrome patients. All three abnormal groups showed hyperinsulinemia compared to normal. The basal insulin delivery rates were calculated as 7.0 +/- 0.3 mU/min/m2, with a threefold increase in obese and in hyperthyroid and no significant change in Cushing's syndrome patients. Insulin clearance correlated well with insulin responsiveness (r = .65, P less than 0.001), but poorly with insulin sensitivity (r = .36).(ABSTRACT TRUNCATED AT 250 WORDS)     

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

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

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 +/- 2.7 years, body mass index 47.1 +/- 1) by the euglycemic clamp technique (40 microU/m2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 +/- 2.5 years, body mass index 23 +/- 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls (P less than 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg X min-1 of fat free mass was significantly reduced in the massively obese patients compared to the controls (P less than 0.001). Similarly, the M/I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients (P less than 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 +/- 51 v 467 +/- 55 mumol/L, P less than 0.05; glycerol 97 +/- 9 v 59 +/- 11 mumol/L, P less than 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistance to insulin suppression of plasma free fatty acids in liver cirrhosis

Insulin action on carbohydrate metabolism is known to be reduced in liver cirrhosis. However, little is known about the effect of insulin on free fatty acid (FFA) metabolism in these patients. To investigate this aspect we performed a two-step insulin euglycemic clamp in 11 cirrhotic patients and 6 controls. Insulin was infused at 0.25 mU/Kg min from 0 to 100 min and at 1 mU/Kg from 100 to 200 min. The FFA lowering capacity of insulin was studied during the first step; the glucose metabolizing capacity (M) was evaluated during the second step. In the cirrhotic patients, the M value was lower than in controls (3.91 +/- 0.48 vs 7.75 +/- 1.09 mg/kg/min, respectively). During the low insulin infusion, FFA and glycerol plasma levels were decreased in both groups. However, the ability of insulin to suppress plasma FFA and glycerol was lower in cirrhotics than in controls. In fact, at 100 min, FFA were 50% of basal values in cirrhotics and 20% in controls (p less than 0.01), while glycerol plasma levels decreased to 70% of basal values in patients and to 56% in controls. The slope of the linear regression obtained between Ln-FFA concentrations vs time was significantly less in cirrhotic patients than in controls (p less than 0.001). In addition, a positive correlation was found between the M value (r = 0.70; p less than 0.01) and the slope of the Ln-FFA in each patient. These findings suggest that in cirrhotic patients the effects of insulin on both FFA and glucose metabolism are reduced.     

Insulin action and insulin secretion in newly diagnosed type 2 diabetic patients

To clarify the insulin action and insulin secretion in newly diagnosed type 2 diabetic subjects, we investigated insulin and C-peptide response to an oral glucose tolerance test (OGTT) in 15 newly diagnosed type 2 diabetic patients and 17 healthy subjects. For insulin action, we found fasting hyperinsulinemia (8.4 +/- 0.8 vs. 6.0 +/- 0.5 microIU/ml, p = 0.014), higher insulin resistance by homeostasis model assessment (HOMA) (4.33 +/- 0.2 vs. 1.34 +/- 0.1 microIU/ml.mmol/l, p < 0.001), and lower insulin sensitivity index (ISI) (51.0 +/- 0.7 vs. 104.0 +/- 0.8, p < 0.001) in newly diagnosed diabetic patients compared to normal subjects. For insulin secretion, the increments of AUCI (area under curve of insulin) and AUCC-P (area under curve of C-peptide) (increment of AUCI: 26.1 +/- 1.4 vs. 82.8 +/- 4.5 microIU/ml.hour, p < 0.001; increment of AUCC-P: 3.9 +/- 0.2 vs. 11.4 +/- 0.6 ng/ml.hour, p < 0.001), insulin secretion by HOMA model (20.7 +/- 1.2 vs. 79.1 +/- 3.8 IU/mol, p < 0.001), and ratio of 30 min increment of fasting insulin to glucose during OGTT (1.14 +/- 0.1 vs. 13.1 +/- 0.5 IU/mol, p < 0.001) were significantly lower in the newly diagnosed diabetic patients than normal subjects. In addition, body mass index (BMI) in our type 2 diabetes is relatively lower (24 +/- 0.65 kg/m2) than those in western countries. These findings revealed poor insulin action and decreased insulin secretion in relatively less obese Taiwanese with newly diagnosed type 2 diabetes.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis

We have examined the hypothesis that insulin insensitivity in hepatic cirrhosis is related to abnormalities of glycogen deposition and skeletal muscle enzyme activities. Otherwise well patients with biopsy-proven hepatic cirrhosis secondary to previous excess alcohol intake were studied. Prior to study, in basal state, patients had identical blood glucose concentrations but raised serum insulin concentrations (cirrhotic: 8.5 +/- 0.8 mU per liter; matched control subjects: 5.7 +/- 0.5 mU per liter, p less than 0.01). Muscle glycogen content, glycogen synthase activity and pyruvate dehydrogenase activity were normal in the basal state. The cirrhotic patients required less glucose to maintain the clamp in response to 0.1 unit per kg per hr insulin (6.7 +/- 0.5 vs. control 8.3 +/- 0.4 mg per kg per min, p less than 0.05) and deposited less glycogen in muscle during the clamp (8.6 +/- 0.5 vs. 12.0 +/- 1.4 mg per gm protein, p less than 0.05). Glycogen deposition correlated with clamp glucose requirement in the cirrhotic patients (r = 0.78, p less than 0.05). The expressed activity of glycogen synthase activity was significantly lower in cirrhotic patients at the end of the clamp (26.5 +/- 1.1% vs. 30.9 +/- 1.6%) and again correlated with clamp glucose requirement (r = 0.82, p less than 0.05). Skeletal muscle pyruvate dehydrogenase activity was not different in patients and control subjects. Insulin insensitivity in hepatic cirrhosis appears to be related to abnormalities of glucose deposition as glycogen in skeletal muscle.     

Hepatic and peripheral insulin resistance following streptozotocin-induced insulin deficiency in the dog

Insulin resistance and insulin deficiency are both present in many patients with diabetes mellitus. We tested the hypothesis that insulin resistance can evolve from a primary lesion of the beta-cell secretory function. Insulin-mediated glucose uptake (insulin clamp), endogenous glucose production, and glucose-stimulated insulin secretion (hyperglycemic clamp) were measured in awake dogs before and four to six weeks after streptozotocin-induced diabetes mellitus. Streptozotocin (30 mg/kg) resulted in a significant rise in the mean fasting plasma glucose concentration from 104 +/- 2 mg/100 mL to 200 +/- 34 mg/100 mL, (P less than 0.05), and a slight decrease in the mean fasting plasma insulin concentration (from 21 +/- 2 microU/mL to 15 +/- 2 microU/mL). Under conditions of steady-state hyperglycemia (+75 mg/100 mL hyperglycemic clamp, insulin secretion was reduced by 75% in the streptozotocin-treated dogs (P less than 0.025), and the total amount of glucose metabolized decreased from 13.56 +/- 1.04 to 4.74 +/- 0.70 mg/min X kg (P less than 0.001). In the postabsorptive state, endogenous glucose production was slightly, although not significantly, higher in the diabetic dogs (3.05 +/- 0.46 v 2.51 +/- 0.22 mg/min . kg), while the glucose clearance rate was 35% lower (P less than 0.001). When the plasma insulin concentration was increased to approximately 45 microU/mL (insulin clamp) while holding plasma glucose constant at the respective fasting levels (99 +/- 1 and 186 +/- 30 mg/100 mL), endogenous glucose production was completely suppressed in control dogs but suppressed by only 51% (1.46 +/- 0.37 mg/min . kg, P less than 0.025) in diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus

To test whether metformin treatment might improve peripheral insulin sensitivity in non insulin dependent diabetes, we measured peripheral glucose uptake in 12 non insulin dependent diabetics before (A) and after 4 weeks (B) of metformin therapy (2 X 850 mg/day) by the hyperinsulinemic clamp technique (80 mU/m2/min). In addition, insulin binding to monocytes was compared between A and B. Diabetic control, evaluated by measurement of fasting blood glucose and glycosylated hemoglobin, was significantly improved by metformin treatment (P less than 0.01). Insulin binding to monocytes was not significantly influenced by metformin (A-4.53% vs. B-5.12%, n.s. at insulin tracer concentration). Peripheral glucose utilisation improved slightly, but significantly after 4 weeks of metformin therapy (A: 4.4 +/- 0.6 mg/kg/min, B: 5.4 +/- 0.8 mg/kg/min, p less than 0.01). Improvement in peripheral glucose utilisation correlated significantly with improved metabolic control, estimated by fasting blood glucose measurements (p less than 0.01).     

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity

Hyperinsulinemia and insulin resistance are commonly seen in obese and non-insulin-dependent diabetes mellitus (NIDDM) patients, suggesting a causal link exists between hyperinsulinemia and insulin resistance. In a previous study, we demonstrated that chronic (28 days) intraportal hyperinsulinemia (50% increase in basal insulin levels) resulted in a decrease in insulin action as assessed by a one-step euglycemic hyperinsulinemic clamp. Since only one dose of insulin was used during the clamp, it was not possible to determine if the decrease in insulin action was due to a change in insulin sensitivity and/or maximal insulin responsiveness. In the present study, insulin resistance was induced as before, but insulin action was assessed in overnight fasted conscious dogs using a four-step euglycemic hyperinsulinemic clamp (1, 2, 10, and 15 mU/kg/min). Insulin responsiveness was assessed before the induction of chronic hyperinsulinemia (day 0), and after 28 days of hyperinsulinemia (day 28). Transhepatic glucose balance and whole-body glucose utilization were measured to allow assessment of both the hepatic and peripheral effects of insulin. Chronic hyperinsulinemia increased basal insulin levels from 13 +/- 2 to 21 +/- 4 microU/mL. After 4 weeks of chronic hyperinsulinemia, maximal insulin-stimulated glucose utilization was decreased 23% +/- 4% (P less than .05) and insulin sensitivity (ED50) was not significantly altered. During the four-step clamp, the liver was a major site of glucose utilization. The liver was responsible for 13% of the total glucose disposal rate on day 0 (2.9 mg/kg/min) at the highest insulin infusion rate (15 mU/kg/min; 2,000 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance and vascular dysfunction in nondiabetic Asian Indians

Asian Indians are at higher risk for diabetes and cardiovascular disease than European Caucasians. To examine the pathophysiology of this increased risk, we measured insulin sensitivity, cardiovascular risk factors, fat distribution, and endothelium-dependent (reactive hyperemia) and -independent (nitroglycerin) vasodilation before and after a 2-h hyperinsulinemic clamp (40 mU/m(2).min) in 25 nondiabetic Asian Indians and 15 Caucasians with similar age and body mass index. Asian Indians had higher fasting insulin than Caucasians (6.7 +/- 0.8 vs. 3.7 +/- 0.3 microU/ml, P = 0.007) but similar FPG (90 +/- 2 vs. 88 +/- 2 mg/dl). Glucose uptake during the clamp was markedly reduced in Asian Indians vs. Caucasians (4.5 +/- 0.3 vs. 7.5 +/- 0.4 mg/kg x min, P < 0.0001). During the clamp, basal brachial artery diameter increased less in Asian Indians vs. Caucasians (2.6 +/- 1.0 vs. 5.7 +/- 1.0%, P = 0.04), and the reduction was correlated with the impairment in insulin sensitivity (r = 0.38, P = 0.04). In contrast, vasodilatory responses to reactive hyperemia and nitroglycerin were similar in Asian Indians and Caucasians both before and during hyperinsulinemia. Plasminogen activator inhibitor-1 and FFA were significantly elevated and adiponectin was significantly lower in Asian Indians vs. Caucasians, and there were trends toward higher low-density lipoprotein and triglycerides, lower high-density lipoprotein, and increased total, sc, and visceral fat. These risk factors were all significantly correlated with insulin sensitivity. Thus, apparently healthy Asian Indians have severe insulin resistance, dyslipidemia, elevated plasminogen activator inhibitor-1, impaired insulin-mediated vasodilation, and trends toward altered body fat distribution. These abnormalities may contribute to the increased risk of diabetes and cardiovascular disease in this population.