Insulin action and hepatic glucose cycling in essential hypertension.

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ketone bodies on basal and insulin-stimulated glucose utilization in man

Using the euglycemic clamp technique, we investigated the effects of high ketone body levels on basal and insulin-stimulated glucose utilization in normal subjects. Infusion of sodium acetoacetate in the postabsorptive state raised ketone body levels from 150 +/- 20 (+/- SE) mumol/liter to more than 1 mmol/liter. Endogenous glucose production declined from 2.71 +/- 0.20 mg kg-1 min-1 to 1.75 + 0.26 (P less than 0.01) and glucose utilization from 2.71 +/- 0.20 to 1.98 +/- 0.17 mg kg-1 min-1 (P less than 0.01), while blood glucose was maintained at the initial level by the infusion of glucose. There were no changes in plasma glucagon, insulin, or C-peptide. Plasma nonesterified fatty acids (P less than 0.01) and blood glycerol (P less than 0.01) and alanine (P less than 0.05) decreased, while blood lactate increased (P less than 0.01). Infusion of sodium bicarbonate had no effect on glucose kinetics. The decreases in glucose utilization and endogenous glucose production during the infusion of acetoacetate were not modified when the fall of plasma nonesterified fatty acids was prevented by iv heparin injection. During control euglycemic hyperinsulinemic clamps (1 and 10 mU kg-1 min-1 insulin infusion), endogenous glucose production was suppressed at the lowest insulin infusion rate; glucose utilization increased first to 7.32 +/- 0.96 mg kg-1 min-1 and then to 16.5 +/- 1.27 mg kg-1 min-1. During euglycemic hyperinsulinemic clamps with simultaneous sodium acetoacetate infusion, similar insulin levels were attained; endogenous glucose production was also suppressed at the lowest insulin infusion rate, and insulin-stimulated glucose utilization rates (7.93 +/- 1.70 and 15.80 +/- 1.30 mg kg-1 min-1) were not modified. In conclusion, acetoacetate infusion decreased basal, but not insulin-stimulated, glucose utilization. The increase in lactate during acetoacetate infusion in the postabsorptive state suggests that ketone body acted by decreasing pyruvate oxidation.     

Insulin resistance in multiple aspects of intermediary metabolism in myotonic dystrophy

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U.kg-1.h-1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 +/- 2.0 v 2.3 +/- 0.2 mU/L, P less than .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 +/- 0.02 v 0.05 +/- 0.01 mmol/L, P less than .05), lactate (1.14 +/- 0.12 v 0.77 +/- 0.07 mmol/L, P less than .02), and pyruvate (0.08 +/- 0.01 v 0.05 +/- 0.01 mmol/L, P less than .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P less than .02) and C-peptide (F = 5.1, P less than .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P less than .01), pyruvate (7.8, P less than .02), and glycerol (F = 7.5, P less than .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 +/- 0.4 v 5.5 +/- 0.7 mL.kg-1.min-1, P less than .05), indicating impaired peripheral glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion.

Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 +/- 11.5 v 22.1 +/- 2.2 kg.m-2; mean +/- SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 +/- 3.8 v 2.4 +/- 3.0 mU.L-1, P less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) at the highest infusion rate was similar (1,048 +/- 425 v 1,018 +/- 357 mL.m-2.min-1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 +/- 108 v 444 +/- 68 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 +/- 0.5 v 1.9 +/- 0.5 mmol.L-1, P less than .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL.m-2.min-1/mU.L-1, P less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Marked impairment of the effect of hyperglycaemia on glucose uptake and glucose production in insulin-dependent diabetes

The effect of hyperglycaemia per se on glucose utilization and glucose production was evaluated in 12 patients with insulin-dependent diabetes and in 9 non-diabetic control subjects. In diabetic patients normoglycaemia was maintained during the night preceding the study by a variable intravenous insulin infusion. During the study endogenous insulin secretion was suppressed by somatostatin (300 micrograms h-1) and replaced by infusion of insulin (0.2 mU kg-1 min-1). Glucose utilization and hepatic glucose production rates were quantified at two plasma glucose concentrations (6.7 and 16.7 mmol l-1) using the two-step sequential hyperglycaemic clamp technique in combination with 3-3H-glucose tracer infusion. Duration of each step was 120 min. In diabetic patients glucose utilization, at a glucose concentration of 6.7 mmol l-1, was not different from normal (mean +/- SE: 2.9 +/- 0.2 vs 3.6 +/- 0.3 mg kg-1 min-1, 0.05 less than p less than 0.10), but the response to marked hyperglycaemia was significantly reduced (5.4 +/- 0.5 vs 9.4 +/- 1.0 mg kg-1 min-1, p less than 0.01). Hepatic glucose production was also normal at 6.7 mmol l-1 (1.4 +/- 0.1 vs 1.4 +/- 0.1 mg kg-1 min-1, NS), but whereas in control subjects glucose production was suppressed during hyperglycaemia of 16.7 mmol l-1 (0.3 +/- 0.4 mg kg-1 min-1, p less than 0.01), a slight increase was observed in diabetic patients (2.0 +/- 0.2 mg kg-1 min-1, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects. Studies at physiologic and supraphysiologic hormone levels

To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU.kg-1.min-1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU.kg-1.min-1) sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16, 22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates [( 3(-3)H]glucose) in uraemic patients compared with controls (P less than 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 +/- 1.0 versus 1.4 +/- 0.3 (mean +/- 1 SD), -0.3 +/- 0.7 versus 0.7 +/- 0.3, and -1.1 +/- 0.7 versus 0.2 +/- 0.6 mg.kg-1.min-1; P less than 0.05, P less than 0.01 and P less than 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 +/- 0.3 versus 2.2 +/- 0.6 mg.kg-1.min-1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above approximately equal to 30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng.kg-1.min-1, respectively, for 210 min concomitant with somatostatin (125 micrograms/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 +/- 0.8 versus 4.8 +/- 1.0 mg.kg-1.min-1; P less than 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.     

Interactions of glucagon and free fatty acids with insulin in control of glucose metabolism

To study the interactions of physiological glucagon and free fatty acids (FFA) concentrations with insulin in the control of glucose metabolism, we determined in normal subjects the response of endogenous glucose production (EGP) and glucose utilization (Rd) to a progressive and moderate increase of insulinemia in the presence of glucagon and FFA levels either decreased (somatostatin [SRIF] and insulin infusion, C test) or maintained to normal postabsorptive values isolated (SRIF + insulin + glucagon infusion, G test; SRIF + insulin + Intralipid infusion, IL test) or in association (SRIF + insulin + glucagon + Intralipid infusion, IL + G test). Compared with the C test, maintenance of glucagon level had only small and inconsistent effects on glucose Rd, but induced a shift to the right of the dose-response curve to insulin of EGP (apparent ED50: C test, 10.9 mU.L-1; G test, 15.2 mU.L-1). Intralipid infusion resulted, whether glucagon was substituted or not, in a near total suppression of the insulin-induced increase of glucose Rd (Rd at the end of the tests: C test, 6.13 +/- 0.85 mg.kg-1.min-1; G test, 7.29 +/- 0.87 mg.kg-1.min-1; IL test, 3.30 +/- 0.65 mg.kg-1.min-1; IL + G test, 3.57 +/- 0.42 mg.kg-1.min-1). In the absence of glucagon, substitution Intralipid infusion also antagonized the action of insulin on EGP. However, this effect was no longer apparent when glucagon was replaced (dose-response curve to insulin of EGP during the G and the IL + G test were comparable).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of intraperitoneal insulin delivery on carbohydrate metabolism in type 1 (insulin-dependent) diabetic patients.

Patients with type 1 diabetes are usually given insulin subcutaneously, but this does not mimic the physiological route of pancreatic insulin release, which may be better achieved with intraperitoneal insulin. Five C-peptide negative type 1 diabetic patients were studied on two occasions, once with intravenous (IV) and once with intraperitoneal (IP) insulin. Normoglycaemia was maintained from 1700 h with variable insulin infusion, and glucose turnover and recycling assessed from 0600 to 0800 h. A 4-h hyperinsulinaemic (25 mU kg-1 h-1) euglycaemic clamp was then performed, with IP or IV insulin delivery. During the night similar insulin infusion rates were needed to achieve equal blood glucose concentrations. Glucose turnover was identical (IV: 2.4 +/- 0.2 vs IP: 2.3 +/- 0.1 mg kg-1 min-1) (+/- SE) with glucose/carbon recycling 8.8 +/- 4.7 and 12.8 +/- 2.9% (NS). Blood lactate, pyruvate and alanine concentrations were significantly higher with IP than IV insulin (P less than 0.05). During the clamp, insulin concentration was 28 +/- 3 mU/l with IV insulin and 15 +/- 1 mU/l with IP insulin (P less than 0.05) and glucose requirement 2.0 +/- 0.5 and 0.8 +/- 0.3 mg kg-1 min-1, respectively (P less than 0.05). Glucose carbon recycling was higher with IP insulin (P less than 0.05). We conclude that: (1) in type 1 (insulin-dependent) diabetic patients hepatic glucose production could be normalized with both routes of insulin administration, and (2) at the same insulin infusion rate, the relative peripheral hypoinsulinaemia with IP route is sufficient to increase the rate of release of gluconeogenic precursors, or decrease their hepatic uptake.     

Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men.

To test whether clinically stable human immunodeficiency virus (HIV) infection, like other infections, is associated with insulin resistance and increased insulin clearance, we measured the sensitivity to insulin and insulin clearance using the euglycemic insulin clamp technique in 10 clinically stable outpatients with symptomatic HIV infection (Centers for Disease Control [CDC] group IV) and 10 healthy controls. During administration of 0.8 and 4 mU insulin.kg-1.min-1, HIV-infected men had 40% (P less than .02) and 83% (P less than .01) higher rates of insulin clearance when compared with healthy controls. Despite significantly lower steady-state insulin concentrations (42 +/- 2 v 52 +/- 4 microU/mL, P less than .05, and 255 +/- 17 v 392 +/- 14 microU/mL, P less than .001, patients v controls), patients and controls had similar total glucose uptake (7.99 +/- 0.81 v 7.92 +/- 0.44 mg.kg-1.min-1 and 14.00 +/- 0.81 v 13.65 +/- 0.65 mg.kg-1.min-1, patients v controls). In the postabsorptive state, no differences were found between patients and controls in insulin levels (7 +/- 1 microU/mL in both) and endogenous glucose production (2.52 +/- 0.07 and 2.24 +/- 0.17 mg.kg-1.min-1, respectively), but plasma glucose levels in the patients (5.02 +/- 0.15 mmol/L) were significantly lower when compared with controls (5.46 +/- 0.14 mmol/L, P less than .05). The results indicate that HIV-infected men have increased rates of insulin clearance and increased sensitivity of peripheral tissues to insulin, which makes HIV infection unique with regard to glucose and insulin metabolism.     

Direct assessment of splanchnic uptake and metabolic effects of human and porcine insulin

The hepatic vein catheterization technique was used to quantitate the splanchnic uptake and the metabolic effects of biosynthetic human insulin (BHI) and porcine insulin (PI) in normal man. BHI and PI were infused into a peripheral vein (0.9-1.3 mU kg-1 min-1) for 60 min together with SRIH (0.6 mg/h) to inhibit endogenous insulin secretion and glucose to induce moderate hyperglycemia (9-10 mmol/liter). During the infusion period, arterial-hepatic venous difference of plasma C-peptide as well as splanchnic C-peptide output fell by more than 98% indicating virtually complete cessation of endogenous insulin release. Under these conditions, the arterial-hepatic venous differences in plasma insulin concentrations represent a valid and direct measurement of splanchnic insulin uptake. During BHI infusion, arterial insulin levels rose to 82 +/- 11 (SE) microU/ml (range: 33-105 microU/ml). Splanchnic insulin uptake paralleled the rise of arterial insulin, reaching 430 +/- 72 microU kg-1 min-1 at 60 min. No appreciable difference between BHI and PI was demonstrable. A highly significant correlation between arterial insulin concentrations and splanchnic insulin uptake was found (r = 0.816; P less than 0.001). Accordingly, both fractional splanchnic insulin extraction and splanchnic insulin clearance remained unchanged throughout insulin infusion and averaged 70 +/- 4% and 5.3 +/- 2 ml kg-1 min-1, respectively. With BHI infusion, splanchnic glucose balance (-8.5 +/- 0.9 mumol kg-1 min-1, basal) became positive (7.3 +/- 1 mumol kg-1 min-1). In contrast, basal splanchnic lactate uptake was inhibited by BHI and there was lactate production (from 3.4 +/- 0.9 to -1.7 +/- 1.4 mumol kg-1 min-1). Similar changes in splanchnic glucose and lactate metabolism occurred during PI infusion. These studies indicate that: 1) A considerable amount of insulin (70 +/- 4%) is extracted by the splanchnic bed on a single passage, after exogenous administration of either human insulin or PI; 2) over a physiological range of insulin concentrations (33-105 microU/ml) a linear relationship exists between arterial insulin concentrations and splanchnic insulin removal; and 3) BHI and PI do not differ appreciably with respect to their uptake and metabolic effects at the splanchnic level.     

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).     

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.     

Metabolic studies in lipoatrophic diabetes: mechanism of hyperglycemia and evidence of resistance to insulin of lipid metabolism

We determined in 5 control subjects and in one patient with total congenital lipoatrophy (LA) the effect of insulin infusion on glucose flux and some aspects of lipid metabolism. In the post-absorptive state LA had moderate hyperglycemia (9.2 versus 3.80 +/- 0.07 mmol.l-1) and hyperinsulinemia (19 vs 12 +/- 3 mU.l-1) and a massive increase in glucose production (7.51 mg.kg.-1.min-1) and disappearance (7.40 mg.kg-1.min-1) rates (control subjects: 2.29 +/- 0.14 mg.kg-1 min-1). Raising peripheral insulin levels to 28 +/- 3 mU.l-1 suppressed endogenous glucose production in the control subjects whereas in LA significant (2.01 mg.kg-1.min-1) production persisted even when peripheral insulinemia was raised to 58 mU.l-1. Insulin infusion in control subjects increased progressively glucose utilization to a final value of 15.7 +/- 0.7 mg.kg-1.min-1 (corresponding plasma insulin: 482 +/- 44 mU.l-1). Insulin infusion in LA initially lowered glucose level near to normal values and exogenous glucose was infused for an insulin infusion rate of 10 mU.kg-1.min-1; at this insulin infusion rate glucose utilization rate (6.52 mg.kg-1.min-1) was decreased relative to control subjects in spite of higher insulin levels (750 mU.l-1). NEFA, glycerol and ketone bodies (KB) levels were decreased to undetectable levels by insulin infusion in the normal subjects whereas NEFA and glycerol were decreased only in part and KB were not modified in LA. In addition glycerol and KB appearance rates determined in LA were not suppressed by insulin infusion as expected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epinephrine directly antagonizes insulin-mediated activation of glucose uptake and inhibition of free fatty acid release in forearm tissues.

To determine whether the anti-insulin effect of epinephrine is due to a direct antagonism on target tissues or is mediated by indirect mechanisms (systemic substrate and/or hormone changes), insulin and epinephrine were infused intrabrachially in five normal volunteers using the forearm perfusion technique. Insulin (2.5 mU/min) was infused alone for 90 minutes and in combination with epinephrine (25 ng/min) for an additional 90 minutes, so as to increase the local concentrations of these hormones to physiological levels (60 to 75 microU/mL and 200 to 250 pg/mL for insulin and epinephrine, respectively). Systemic plasma glucose and free fatty acids (FFA) concentrations remained stable at their basal values during local hormone infusion. Forearm glucose uptake (FGU) increased in response to insulin alone from 0.8 +/- 0.2 mg.L-1.min-1 to 4.3 +/- 0.8. Addition of epinephrine completely abolished the insulin effect on FGU, which returned to its preinfusion value (0.7 +/- 0.2). Forearm lactate release was slightly increased by insulin alone, but rose markedly on addition of epinephrine (from 5.2 +/- 0.8 mumol.L-1.min-1 to 17 +/- 2; P less than .02). During infusion of insulin alone, forearm FFA release (FFR) decreased significantly from the postabsorptive value of 1.76 +/- 0.25 mumol.L-1.min-1 to 1.05 +/- 0.11 (P less than .01). Epinephrine addition reverted insulin suppression of FFR, which returned to values slightly above baseline (2.06 +/- 0.47 mumol.L-1.min-1; P less than .05 v insulin alone). The data demonstrate that epinephrine is able to antagonize directly insulin action on forearm tissues with respect to both stimulation of glucose uptake and inhibition of FFA mobilization.     

Effect of acute inhibition of lipolysis on operation of the glucose-fatty acid cycle in hepatic cirrhosis.

Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide (P less than .001) compared with patients receiving the placebo. Acipimox blunted the increase in glucose after oral glucose loading and decreased incremental glucose concentration (from 579 +/- 76 to 445 +/- 65 mmol/min/L, P less than .02) and incremental insulin concentration (from 13.4 +/- 2.5 to 9.0 +/- 1.4 U/min/L, P = .056) in the OGTT. Improvements in classification of glucose tolerance were seen in five subjects. During the IST, significant reductions occurred in steady-state blood glucose (to 8.8 +/- 1 mmol/L, P less than .02) and C-peptide (to 3.0 +/- 0.5 nmol/L, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Glucose utilization in Type 1 (insulin-dependent) diabetes: Evidence for a defect not reversible by acute elevations of insulin

It has long been assumed that replacement of insulin in insulin-deficient diabetic patients will normalise glucose utilization. In this study, glucose utilization was measured in nine long-standing, poorly controlled diabetic patients and five control subjects, matched for age (33 +/- 3 versus 33 +/- 2 years) and ponderal index (22.9 +/- 1.3 versus 21.7 +/- 1.0). Glucose uptake was measured during steady state insulinaemia in the diabetic patients and control subjects, at euglycaemia (5.5 +/- 0.5 versus 5.4 +/- 0.3 mmol/l, respectively) and moderate hyperglycaemia (11.8 +/- 0.9 versus 10.2 +/- 0.7 mmol/l, respectively). At euglycaemia with similar free insulin levels (50 +/- 19 versus 43 +/- 9 mU/l; p greater than 0.6), the diabetic patients utilized less glucose than the control subjects (27.8 +/- 4.2 versus 56.4 +/- 5.7 mumol.kg-1.min-1;.p less than 0.005). During hyperglycaemia, the diabetic patients utilized almost as much glucose as the control subjects did at euglycaemia (49.9 +/- 6.4 versus 56.4 +/- 5.7 mumol.kg-1.min-1, respectively). In the control subjects, a 1-mmol/l rise in glucose concentration (with insulin remaining constant) resulted in a 12.3 +/- 1.3 mumol.kg-1.min-1 rise in glucose utilization. In contrast, in the diabetic patients, a 1-mmol/l rise in blood glucose resulted in a rise in glucose utilization of only 3.8 +/- 0.8 mumol.kg-1.min-1 (p less than 0.001), in the presence of similar concentrations of plasma insulin. This defect of glucose utilization in Type1 diabetic patients could not be reversed by acutely raising insulin to 247 +/- 23 mU/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin-mediated glucose disposal in type 1 (insulin-dependent) diabetic subjects treated by continuous subcutaneous or intraperitoneal insulin fusion

In order to determine if intraperitoneal insulin infusion could improve the insulin resistance of type 1 diabetic patients we have used the englycaemic insulin clamp technique in order to study the effects of insulin on glucose disposal in four C peptide negative type 1 diabetic patients treated by continuous subcutaneous or intraperitoneal insulin infusion and in five control subjects. Compared to control subjects, the diabetic patients treated by subcutaneous insulin infusion had a decreased maximal capacity of glucose utilization (diabetics: 12.6 +/- 0.3 mg.kg-1.min-1; controls: 15.7 +/- 0.7 mg/kg-1.min-1, p less than 0.01) and a trend towards higher half-maximally effective insulin concentrations (diabetics: 70 +/- 11 mU/l-1, controls: 48 +/- 4 mU/l-1). Treatment of the diabetic patients by intraperitoneal insulin infusion for 2 months decreased their mean peripheral free insulin levels (during subcutaneous infusion: 23.5 +/- 2.2 mU/l-1; during intraperitoneal infusion: 18.4 +/- 1.4 mU/l-1, p less than 0.05). However, mean daily insulin requirements were not decreased (during subcutaneous infusion: 0.59 +/- 0.05 U/kg-1.day-1; during intraperitoneal infusion: 0.57 +/- 0.03 U/kg-1.min-1). Moreover, the diabetic patients had a consistently lower maximal capacity of glucose utilization (12.6 +/- 0.7 mg kg-1.min-1) than control subjects (p less than 0.01) without modification of the half-maximally effective insulin concentration (62 +/- 10 mU.l-1). In conclusion, the only benefit of intraperitoneal insulin infusion was a reduction of peripheral free insulin levels; this decrease of peripheral insulinaemia was not associated with an improvement in the insulin resistance of diabetic patients.     

Glucose metabolism in experimental hyperthyroidism: intact in vivo sensitivity to insulin with abnormal binding and increased glucose turnover

The characteristics of the dose response of insulin on the glucose turnover rate and erythrocyte insulin binding parameters were determined in five normal men before and during experimentally induced hyperthyroidism [L-T4 (2 micrograms kg-1 day-1) for 4 weeks with additional L-T3 (1 microgram kg-1 day-1) for the following 3 weeks]. Hyperthyroidism was characterized by significant rises in T3 from 1.92 +/- 0.17 (+/- SEM) to 3.66 +/- 0.17 nmol/liter (P less than 0.01) and resting metabolic rate from 39 +/- 0.7 to 48 +/- 1 watt/m2 (P less than 0.001). While the subjects received a diet adapted to the metabolic rate, blood glucose rose from 3.8 +/- 0.07 to 4.46 +/- 0.11 mmol/liter (P less than 0.05) without a significant change in plasma insulin. During the insulin dose-response study, glucose infusion rates were unaltered by hyperthyroidism, and neither the maximum effect nor the sensitivity to insulin was altered. Glucose turnover rate, measured using [6,6-2H2]glucose as tracer, was determined in the basal state and during the 0.4 mU kg-1 min-1 insulin infusion. In the basal state, it was significantly increased by hyperthyroidism (control, 2.3 +/- 0.1; hyperthyroidism, 3.7 +/- 0.1 mg kg-1 min-1). During the insulin infusion, hepatic glucose production was totally suppressed before T4 and T3 treatment, but was 0.96 +/- 0.39 mg kg-1 min-1 during T4 and T3 treatment. A marked decrease in the insulin binding affinity to erythrocytes was found without a change in the insulin receptor number. In conclusion, glucose metabolism in experimental hyperthyroidism is characterized by 1) increases in basal glucose production and utilization; 2) antagonism between the effect of insulin and hyperthyroidism at the hepatic level; and 3) lack of peripheral insulin resistance in spite of marked alteration in erythrocyte insulin binding affinity.     

The action profiles of human NPH insulin preparations

The complete time-action profiles of four subcutaneously injected human NPH insulin preparations (Protaphane HM/Novo; Insulatard Human/Nordisk; Huminsulin Basal/Eli Lilly; Basal H-Insulin/Hoechst) have been investigated by means of the euglycaemic clamp technique (blood glucose 5.0 mmol l-1). Six normal male subjects were connected to a Biostator on five occasions in randomized order including a control study without insulin injection. A stable basal insulin level of about 10 mU l-1 was established by means of a low dose insulin infusion (0.1 mU kg-1 min-1) which subsequently suppressed C-peptide by 35 +/- 19% (mean +/- SD) to levels of around 0.3 nmol l-1. Twelve units of NPH insulin were injected subcutaneously into the abdominal wall and glucose infusion rates were monitored for 19 h. In the control study, the mean glucose infusion rate was 1.11 +/- 0.60 (range 0.32-1.95) mg kg-1 min-1. Maximal glucose infusion rates, reached 5-7 h after injection, were comparable (4.3-4.9 mg kg-1 min-1) for the four different preparations used. Glucose infusion rates returned to basal rates within the 19 h study period. Mean plasma free insulin levels peaked at 17.5-18.6 mU l-1 3-4.5 h after injection and returned to basal levels within 16 h. The time ranges of greater than 90, greater than 75, greater than 50, and greater than 25% of maximal insulin action (as estimated from glucose infusion rates) revealed no significant differences between the four insulin preparations tested. No significant insulin action was observed beyond 17 h after insulin injection of any preparation.