J. P. Felber

The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization

The effect of insulin on the disposal of intravenous glucose was examined employing the euglycemic insulin clamp technique in 24 normal subjects. When the plasma insulin concentration was raised by approximately 100 μU/ml, total glucose metabolism rose to 6.63 ± 0.38 mg/kg · min. Basal splanchnic (hepatic venous catheter technique) glucose production, 2.00 increased only slightly. These results suggest that the ability of higher doses of insulin to further stimulate glucose metabolism is primarily the result of increased glucose storage by peripheral tissues, most likely muscle. 0.15 ± mg/kg · min, reverted to a small net glucose uptake which averaged 0.33 mg/kg · min over the ensuing 2 h. This represented only 5% of the total glucose metabolized. In contrast, leg (femoral venous catheterization) glucose uptake rose from 1.18 ± 0.14 to 8.40 ± 1.06 mg/kg of leg wt. per min. If all muscles in the body respond similarly to those in the leg, muscle would account for 85% of the total glucose metabolism. To determine the relative contributions of glucose oxidation versus glucose storage by peripheral tissues following hyperinsulinemia, we performed euglycemic insulin clamp studies in combination with indirect calorimetry. Basal glucose oxidation, 1.21 ± 0.10 mg/kg min, rose to 2.28 ± 0.16 (P < 0.01), and this increase above baseline accounted for only 20% of the total glucose metabolized, 5.44 ± 0.38 mg/kg · min. Following insulin, glucose storage increased to 3.18 ± 0.34 mg/kg min and was responsible for 59% of the total glucose metabolized. These results indicate that the primary effect of insulin on muscle tissue is to enhance glucose storage, presumably as glycogen. When a higher degree of hyperinsulinemia (163 ± 19 μl/ml) was created while maintaining euglycemia, total glucose metabolism (7.99 ± 0.58) and glucose storage (5.30 ± 0.80) both increased (P < 0.01) compared with the lower dose insulin clamp study, but glucose oxidation (2.70 ± 0.16 mgμkg min)increased only slightly. These results suggest that the ability of higher doses of insulin to further stimulate glucose metabolism is primarily the result of increased glucose storage by peripheral tissues, most likely muscle.

The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man

The dose-response relationship between plasma insulin concentration and total glucose uptake, glucose oxidation, and glucose storage was examined in 22 healthy young volunteers by employing the euglycemic insulin clamp technique in combination with indirect calorimetry. Insulin was infused at five rates to achieve steady-state hyperinsulinemic plateaus of 62 ± 4, 103 ± 5, 170 ± 10, 423 ± 16, and 1132 ± 47 μU/ml. With increasing plasma insulin concentrations within the physiologic range, there was a linear increase in glucose uptake with a half maximally effective insulin concentration of 72 μU/ml. Glucose uptake by all tissues of the body reached 80% of its maximum value (12.6 mg/kg · min) at a plasma insulin concentration of ∼200 μU/ml. In contrast to total glucose uptake, glucose oxidation plateaued more quickly, achieved a maximum rate of only 4.0 mg/kg · min, and displayed a lower half maximally effective insulin concentration of 40 μU/ml. The increase in glucose uptake with progressively increasing plasma insulin levels was primarily the result of an increase in glucose storage, with a half maximally effective insulin concentration of 105 μU/ml and maximum rate of 8.7 mg/kg · min. Glucose storage represented over 60–70% of total glucose uptake at all insulin concentrations. After achieving maximum rates of insulin-mediated glucose uptake (plasma insulin concentration = 1132 μU/ml), hyperglycemia (+125 mg/dl) was superimposed on hyperinsulinemia to further enhance glucose transport. Under these conditions, total glucose uptake (32.5 mg/kg · min, P < 0.001) was markedly augmented but no significant increase in glucose oxidation was observed. These results indicate a true saturation of the glucose oxidation pathway. With pro-gressively increasing doses of insulin, the glucose storage represents the major route of glucose disposal.

7 Indirect calorimetry

Summary Indirect calorimery is a method which allows the non-invasive measurement of enery expenditure and substrate utilization in humans. The procedure is described and the main equations to calculate energy expenditure and substrate utilization are presented. The limitations of the method include physiological effects, such as hyperventilation, and the influence of metabolic processes such as gluconeogenesis, ketogenesis and lipogenesis. The general principle is that intermediate processes do not influence overall conclusions, provided that the intermediate substrates which are formed do not accumulate within the body or are not excreted. Continuous measurements of metabolic rate and respiratory quotient using the ventilated hood system have been carried out during the last 5 years to study carbohydrate and lipid metabolism in lean subjects, in obese and diabetic patients. By using the euglycaemic insulin clamp technique or by giving oral glucose loads, it has been shown that the main effect of insulin on carbohydrate metabolism is to stimulate glucose storage. By raising plasma free fatty acid levels with a neutral fat infusion in lean subjects, both glucose oxidation and glucose storage were impaired during euglycaemic insulin clamps. Glucose storage was found to be markedly impaired in non-diabetic obese patients, during euglycaemic insulin clamps in the presence of elevated lipid oxidation. In obese diabetic patients, the impairment in glucose storage was more pronounced than in non-diabetic obese; this defect was particularly marked during euglycaemic insulin clamps, but it was also present after an oral glucose load. It is concluded that impairment of glucose storage is a major defect of glucose utilization in type II diabetes.

Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry

SummaryGlucose disposal of a 100 g glucose load has been determined in 26 obese compared with 10 non-obese subjects by means of a new application of continuous indirect calorimetry. The obese subjects were divided into 4 groups, according to their degree of glucose intolerance and their insulin response to the glucose load. Through this division it appeared that subjects with no glucose intolerance were moderately obese while the groups with glucose intolerance showed a higher degree of obesity, glucose intolerance increasing with age. The 10 obese subjects with no glucose intolerance (group A) presented values for glucose disposal similar to those of the control subjects. The 4 obese subjects with impaired glucose tolerance (group B) showed no significant changes in glucose storage and in basal oxidation, but a significant decrease in oxidation in response to the load (11±2g vs 19±1 g in the control group, p <0.02). The 6 obese subjects with overt diabetes and elevated insulin response to the glucose load (group C) showed a significant decrease in glucose storage (34±6 g vs 63±1 g, p < 0.001) but not in oxidation. The 6 obese subjects with overt diabetes and decreased insulin response (group D) showed a significant decrease in glucose storage (25±4 g vs 63 ±1 g, p < 0.001) and oxidation (12±1 g, vs 19+1 g, p < 0.005). These observations show that in obese diabetics, glucose intolerance results primarily from decreased glucose storage and to a lesser extent from a decrease in glucose oxidation.

Energy Balance in Elderly Patients after Surgery for a Femoral Neck Fracture

To study energy and protein balances in elderly patients after surgery, spontaneous energy and protein intake and resting energy expenditure (REE) were measured in 20 elderly female patients with a femoral neck fracture (mean age 81 +/- 4, SD, range 74-87 years; weight 53 +/- 8, range 42-68 kg) during a 5-6 day period following surgery. REE, measured over 20-40 min by indirect calorimetry using a ventilated canopy, averaged 0.98 +/- 0.15 kcal/min on day 3 and decreased to 0.93 +/- 0.15 kcal/min on day 8-9 postsurgery (p less than 0.02). REE was positively correlated with body weight (r = 0.69, p less than 0.005). Mean REE extrapolated to 24 hr (24-REE) was 1283 +/- 194 kcal/day. Mean daily food energy intake measured over the 5-day follow-up period was 1097 +/- 333 kcal/day and was positively correlated with 24-REE (r = 0.50, p less than 0.05). Daily energy balance was -235 +/- 351 kcal/day on day 3 (p less than 0.01 vs zero) and -13 +/- 392 kcal/day on day 8-9 postsurgery (NS vs zero) with a mean over the study period of -185 +/- 289 kcal/day (p less than 0.01 vs zero). When an extra 100 kcal/day was allowed for the energy cost of physical activity, mean daily energy balance over the 5-day study period was calculated to be -285 +/- 289 kcal/day (p less than 0.01 vs zero). Measurements of total 24-hr urinary nitrogen (N) excretion were obtained in a subgroup of 14 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin-dependent) diabetic patients

SummaryInsulin resistance is a common feature of Type 2 (non-insulin-dependent) diabetes mellitus. This defect in insulin-mediated glucose metabolism could result from a defect in either glucose oxidation or non-oxidative glucose disposal. To examine this question, euglycaemic insulin clamp studies were performed in 16 normal weight Type 2 and 11 age-matched control subjects. In Type 2 diabetic patients the fasting plasma glucose concentration, 8.39±0.50 mmol/l, was allowed to decline (over 54±6 min) to 5.33±0.11 mmol/l before starting the insulin clamp. Total body glucose uptake was significantly decreased in Type 2 diabetic patients vs control subjects (148±15 vs 264±25 mg/min · m2, p<0.001). Both total glucose oxidation (59±6 vs 89±6 mg/min·m2, p<0.005) and non-oxidative glucose disposal (89±15 vs 179±24 mg/min · m2, p<0.005) were significantly reduced in the Type 2 diabetic patients. Basal glucose oxidation was also reduced in the Type 2 diabetic patients (22±3 vs 38±5 mg/min·m2, p<0.01). In conclusion, during the postabsorptive state and under conditions of euglycaemic hyperinsulinaemia, impairment of glucose oxidation and non-oxidative glucose disposal both contribute to the insulin resistance observed in normal weight Type 2 diabetic patients. Since lipid oxidation was normal in this group of diabetic patients, excessive non-esterified fatty acid oxidation cannot explain the defects in glucose disposal.

Metabolic origin of insulin resistance in obesity with and without Type 2 (non-insulin-dependent) diabetes mellitus

SummaryA metabolic hypothesis is presented for insulin resistance in obesity, in the presence or absence of Type 2 (non-insulin-dependent) diabetes mellitus. It is based on physiological mechanisms including a series of negative feed-back mechanisms, with the inhibition of the function of the glycogen cycle in skeletal muscle as a consequence of decreased glucose utilization resulting from increased lipid oxidation in the obese. It considers the inhibition of glycogen synthase activity together with inhibition of glucose storage and impaired glucose tolerance. The prolonged duration of increased lipid oxidation, considered as the initial cause, may lead to Type 2 diabetes. This hypothesis is compatible with others based on the inhibition of insulin receptor kinase and of glucose transporter activities.

Study on lipid metabolism in obesity diabetes.

Knowing the relationship between obesity and diabetes, the purpose of our work was to study the alterations in lipid metabolism as measured by continuous indirect calorimetry in the course of a 100-g oral glucose-tolerance test in groups of obese patients without and with diabetes, respectively. Seventy-nine obese patients participated in the study. They were divided into four groups according to the degree of carbohydrate intolerance: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with hyperinsulinemic response to the load; group D, diabetes with impaired insulin response. All four groups of patients presented an increase in lipid oxidation, both in the fasting state and during the three-hour glucose tolerance test, when compared to the control group. The lipid oxidation rate was roughly parallel to plasma free fatty acid (FFA) levels. The contribution of lipids to energy expenditure was higher in obese as compared to control subjects. These observations suggest that the larger part taken by lipids in the energy metabolism of both nondiabetic and diabetic obese humans is a consequence of their increased fat stores and that the resulting decrease in carbohydrate metabolism may lead, as a late consequence, to alterations in glucose tolerance. The latter may result in delayed glucose storage and oxidation in the obese patient.

Impaired glucose tolerance and diabetes in obesity: A 6-year follow-up study of glucose metabolism

To investigate the time course of glucose metabolism in obesity 33 patients (21 to 69 years old; body mass index [BMI], 25.7 to 53.3 kg/m2) with different degrees of glucose intolerance or diabetes who had been studied initially and 6 years later were submitted to the same 100-g oral glucose tolerance test (OGTT) with indirect calorimetry. From a group of 13 obese subjects with normal glucose tolerance (NGT), four developed impaired glucose tolerance (IGT); from a group of nine patients with IGT, three developed non-insulin-dependent diabetes mellitus (NIDDM); five of six obese NIDDM subjects with high insulin response developed NIDDM with low insulin response. Five patients had diabetes with hypoinsulinemia initially. As previously seen in a cross-sectional study, the 3-hour glucose storage measured by continuous indirect calorimetry remained unaltered in patients with IGT, whereas it decreased in NIDDM patients. A further decrease in glucose storage was observed with the lowering of the insulin response in the previously hyperinsulinemic diabetics. These results confirm cross-sectional studies that suggest successive phases in the evolution of obesity to diabetes: A, NGT; B, IGT (the hyperglycemia normalizing the glucose storage over 3 hours); C, diabetes with increased insulin response, where hyperglycemia does not correct the resistance to glucose storage anymore; and D, diabetes with low insulin response, with a low glucose storage and an elevated fasting and postload glycemia.

Modifications of glucose storage and oxidation in nonobese diabetics, measured by continuous indirect calorimetry.

A new application of continuous indirect calorimetry is described for measuring the disposal of a glucose load. In a group of 10 normal subjects, 3 h after a 100 g oral glucose load, 20 g glucose was oxidized at basal rate, 19 g in response to the load and 63 g stored, while a decrease of 2 g was observed in the glucose space (GS). In a group of four type I, insulin-dependent diabetics, both glucose oxidation (9 g at the basal rate and 4 g in response to the load) and glucose storage (9 g) were markedly decreased, with the remainder either being lost in the urine (36 g) or remaining in the glucose space (42 g). In a group of eight nonobese type II, non-insulin-dependent diabetics, glucose oxidation both at the basal rate and in response to the load was slightly decreased (13 and 14 g, respectively) and glucose storage decreased to 40 g. These results suggest that, in type I diabetics, complete insulin deficiency seriously impairs two major mechanisms regulating glucose homeostasis, i.e., glucose storage and oxidation, while, in type II diabetics, the remaining insulin secretion attentuates these disturbances.