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This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.

Diabetic patients are more prone to develop atherosclerosis and its complications than non diabetics. This is demonstrated by several clinico-pathological and epidemiological observations (1–3). One of the most accurate of these is the Framingham study which clearly demonstrates that the average annual incidence of vascular disease is higher in diabetics at all age groups, in both sexes and in all main arterial districts (4).

This study attempts to evaluate whether the putative excess risk of cardiovascular disease in individuals with impaired glucose tolerance (IGT) can be explained by the clustering of other major cardiovascular risk factors after controlling for obesity. The study population was 1376 male and female employees of a Naples telephone company who had participated in a health survey in which an oral glucose tolerance test (OGTT) was given. After excluding treated hypertensives, we recruited all 65 individuals with IGT and 125 euglycemic controls matched for gender, age, and weight. Systolic and diastolic blood pressure was significantly higher in individuals with IGT (134 +/- 16 vs 127 +/- 15 mm Hg, p less than 0.001; 87 +/- 10 vs 84 +/- 8 mm Hg, p less than 0.05 (M +/- SD). Blood lipids were similar in the two groups (total cholesterol was 214 +/- 34 vs 218 +/- 40 mg/dl; HDL cholesterol was 39 +/- 9 vs 40 +/- 10 mg/dl; total triglyceride was 145 +/- 58 vs 135 +/- 63 mg/dl). Serum insulin values (fasting or at 1 or 2 hours after 75 g of oral glucose) were also similar. The number of persons currently smoking was significantly lower among individuals with IGT (30% vs 47%, p less than 0.025) but the percentage of exsmokers was identical in the two groups. We conclude that, among the possible cardiovascular risk factors investigated, blood pressure is the only one significantly associated with IGT independent of matched variables and antihypertensive treatment.

The concentrations of glucose and insulin were determined with high precision at half minute intervals in arterial and deep forearm vein blood after a bolus injection of glucose (4 g), followed by a constant i. v. infusion (200 mg/min), in four healthy subjects. The values for the deep vein were corrected for the transit time, which was determined by injection of Cardio-green. Arterial glucose peaked at the end of the bolus injection, venous glucose 1 1/2 min later. Arterial insulin reached its maximum later than glucose, after 2 1/2–4 min. The venous insulin reached its maximum later and was much lower than the arterial level, in two cases only around 50% of the arterial concentration. It is concluded that early after glucose administration there is a considerable extraction of both glucose and insulin by the forearm. Since the insulin extraction was quite variable venous insulin concentrations cannot be used for the assessment of early insulin response to glucose.

To explore the association of the Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 with severe obesity and the features of the metabolic syndrome in a population-based sample of Caucasians.The study is based on a case-control design: 95 non-diabetic severely obese (body mass index, BMI35 kg/m2) cases and 280 normal weight (BMI25 kg/m2), age- and sex-matched controls selected from the same population were studied. Height, weight, waist circumference, as well as blood pressure were measured according to a standard protocol. BMI at age 25 y was calculated on the basis of current height and reported weight at age 25 y Biochemical measurements included fasting glucose, triglycerides, high-density lipoprotein cholesterol and insulin. DNA analysis was conducted by PCR and gel electrophoresis.Age and gender distribution were similar in obese and normal weight participants. The percentage of people with the Pro12Ala mutation was not significantly different in obese or normal weight participants (20% and 15%, respectively; P = 0.32). Conversely, in obese participants with obesity starting in early adulthood (ie with BMI at age 25 above 26.9kg/m2 which represents the median of the whole obese group), the Pro12Ala mutation was observed significantly more frequently than in the normal weight controls (29% vs 15%; chi square = 4.5, P0.05; odds ratio 2.4; 95% CI 1.03-5.36). No association of the Pro12Ala variant with any of the component of the metabolic syndrome measured in the study was observed in either obese, juvenile obese or normal weight participants.Results of this study indicate that the Pro12Ala mutation does not play a major role as a determinant of severe obesity and/or features of the metabolic syndrome in the general population. However, this mutation may be of greater importance as a contributor to early onset obesity.

To evaluate whether the same amount of carbohydrate (CHO) in different foods gives different glycaemic responses when consumed in the context of a real meal, seven diabetic patients were given in a random order and on alternate days three test meals of identical composition. Each meal consisted of a fixed part to which a 50 g CHO portion of either bread (90 g) or spaghetti (65 g) or potatoes (285 g) was added. The glycaemic response was significantly higher after ingestion of bread than after the spaghetti meal both at 2 (5.9 +/- 0.8 vs 4.3 +/- 0.7 mmol/l X hour, p less than 0.05) and at 5 hours (16.5 +/- 3.6 vs 9.8 +/- 2.3 mmol/l X hour, p less than 0.05). The glycaemic response to the potato meal was similar to that for bread at 2 hours (6.2 +/- 1.2 mmol/l X hour, p less than 0.05 vs spaghetti) and intermediate between the two other test meals at 5 hours (14.6 +/- 4.3 mmol/l X hour). Meal planning for diabetic patients should be based not only on the biochemical properties but also on the glycaemic response to the food.

The relationship between impaired glucose tolerance (IGT) and blood lipid levels was examined in 65 IGT individuals and in two control groups: control group I, composed of age-, sex-, and body weight-matched controls, and control group II, including normal subjects matched for sex and age but with normal body mass index. IGT individuals were found to have significantly higher total triglyceride (Tg) values compared with normal weight controls (P < 0.001), while no difference was found between IGT and control group I. Total cholesterol levels were similar in IGT and each of the control groups. No significant correlation was found between serum lipoproteins and blood glucose levels either fasting or after load.

The effect of hyperglycemia per se on glucose uptake by muscle tissue was quantitated in six controls and six type II diabetics by the forearm technique, under conditions of insulin deficiency induced by somatostatin (SRIF) infusion (0.7 mg/h). Blood glucose concentration was clamped at its basal value during the first 60 min of SRIF infusion and then raised to approximately 200 mg/dl by a variable glucose infusion. Plasma insulin levels remained at or below 5 microU/ml during SRIF infusion, including the hyperglycemic period. No appreciable difference between controls and diabetics was present in the basal state as to forearm glucose metabolism. After 60 min of SRIF infusion and euglycemia, forearm glucose uptake fell consistently from 2.1 +/- 0.7 mg X liter-1 X min-1 to 1.0 +/- 0.6 (P less than 0.05) and from 1.7 +/- .2 to 0.4 +/- 0.3 (P less than 0.02) in the control and diabetic groups, respectively. The subsequent induction of hyperglycemia caused a marked increase in both the arterial-deep venous blood glucose difference (P less than 0.02-0.01) and forearm glucose uptake (P less than 0.01-0.005). However, the response in the diabetic group was significantly greater than that observed in controls. The incremental area of forearm glucose uptake was 276 +/- 31 mg X liter-1 X 90 min and 532 +/- 81 in the control and diabetic groups, respectively (P less than 0.02). In the basal state, the forearm released lactate and alanine both in controls and diabetic subjects at comparable rates. No increment was observed after hyperglycemia, despite the elevated rates of glucose uptake. It is concluded that (1) hyperglycemia per se stimulates forearm glucose disposal to a greater extent in type II diabetics than in normal subjects; and (2) the resulting increment of glucose disposal does not accelerate the forearm release of three carbon compounds. The data support the hypothesis that hyperglycemia per se may play a compensatory role for the defective glucose disposal in type II diabetes.

We have recently reported two non-insulin-dependent diabetic patients exhibiting a heterozygous point mutation (R1152-Q) next to the key tyrosine autophosphorylation sites (Y1146, Y1150, Y1151) of the insulin receptor. In the present study, we demonstrate that the Q1152 mutation alters a previously unrecognized consensus sequence in the insulin receptor family of tyrosine kinases. To define the effect of this alteration on insulin receptor function, the mutant insulin receptor (Q1152) was constructed and overexpressed in NIH-3T3 cells. In spite of normal insulin binding, "in vivo" and "in vitro" autophosphorylation as well as transphosphorylation by the wild-type receptor (WT) were deficient in Q1152 as compared with the transfected WT receptors. Insulin-stimulated kinase activity toward poly(Glu, Tyr) 4:1 and the endogenous substrates p120 and p175 were also impaired in Q1152. However, insulin-independent kinase activity of Q1152 was 2-5-fold higher than that of WT. While insulin stimulated 2-deoxyglucose uptake and glycogen synthase activity in WT-transfected cells with a sensitivity proportional to receptor number, no insulin stimulation was observed in Q1152 cells. Similar to the kinase, insulin-independent glycogen synthase activity and 2-deoxyglucose uptake were 2-fold higher in Q1152 than in either WT or parental cells. We conclude that the Q1152 mutation deregulates insulin receptor kinase and generates insulin insensitivity in cells. Alterations in this highly conserved region of the insulin receptor may contribute to non-insulin dependent diabetes mellitin pathogenesis in humans.