A B S T R A C T In rats, muscle glycogen depletion has been associated with increased insulin action. Whether this also occurs in man has not been reported. After 4 d rest, 13 males (E Group) had a percutaneous muscle biopsy of the vastus lateralis muscle followed by a euglycemic clamp at plasma insulin =100 AU/ml and =1,900 MU/ml, with simultaneous indirect calorimetry. This was repeated 1 wk later, but after glycogendepleting exercise the night before the euglycemic clamp. Seven subjects underwent the same protocol but were also re-fed 100 g carbohydrate (CHO) after the exercise (EF group).In both groups, the mean muscle glycogen content was '40% lower (P < 0.01) after exercise compared with the muscle glycogen content measured after rest.In the E group, the mean muscle glycogen synthase activity (percent independent of glucose-6-phosphate) increased threefold (P < 0.001) after exercise, but increased only twofold in the EF group (P < 0.02 between groups). In both groups, the mean basal and insulinstimulated CHO oxidation rates were lower in the postexercise, glycogen-depleted condition compared with the rested, glycogen-replete condition. The mean insulin-stimulated CHO storage rate increased significantly in the E group after exercise but not in the EF group. In the E group, the total insulin-stimulated CHO disposal rate (M) was 17 (P < 0.04) and 10% (P < 0.03) higher after exercise during the low and high dose insulin infusion, respectively. No significant changes in M were observed in the EF group. For all subjects, after rest and exercise, the M correlated with the CHO storage rates during the low (r = 0.80, P < 0.001) and high dose (r = 0.77, P < 0.001) insulin infusions. After exercise, the muscle glycogen synthase activity correlated with the CHO Received for publication 18 March 1983 and in revised form 22 July 1983. storage rate (r = 0.73, P < 0.002; r = 0.75, P < 0.002) during the low and high dose insulin infusions, respectively, and also with M (r = 0.64, P < 0.008; r = 0.57; P < 0.02).

A B S T R A C T To assess possible cellular mechanisms of in vitro insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM), maximum insulin-stimulated glucose transport and utilization and insulin binding were measured in adipocytes isolated from weight-matched normal glycemic subjects and patients with NIDDM. Glucose transport rate was determined by measuring the amount of [U-'4C]-D-glucose taken up by incubating adipocytes at trace concentrations of glucose (300 nM), and glucose metabolism by estimating the amount of lactate, CO2, triglyceride, and total glucose carbons retained in the cells following incubating at 5.5 mM glucose. Insulin binding was measured at 50, 100, and 200 pM [mono'25 -tyrosinyl A,J4insulin. Both maximum insulin-stimulated glucose transport and utilization in adipocytes from diabetic subjects were 40% (P < 0.01) and 32% (P < 0.05) lower, respectively, than values obtained for subjects with normal glucose tolerance. In addition, the maximum capacity of glucose transport was correlated with the maximum capacity of glucose utilization (r = 0.81, P < 0.001). Furthermore, fasting plasma glucose concentrations of diabetic subjects were negatively correlated with both maximum insulin-stimulated glucose transport (r = -0.56, P < 0.05) and glucose utilization (r = -0.67, P < 0.05). Since basal glucose transport in adipocytes from diabetic subjects was also 33% lower than in adipocytes from normal subjects, there was no change in the relative ability of insulin to stimulate glucose transport. However, there was a 64% decrease in the sensitivity of the glucose transport system to insulin (P < 0.05), unrelated to concomitant Address reprint requests to Dr. James E. Foley.

Summary. To determine whether sustained control of hyperglycaemia in Type 2 (non-insulin-dependent) diabetic patients would diminish proteinuria, the effect of hypocaloric diet therapy (500 kcal/day) on proteinuria was assessed in obese, Type 2 diabetic patients (n = 24) and compared with results obtained for obese subjects with normal glucose tolerance (n = 7) and impaired glucose tolerance (n = 6). Diet therapy of similar mean duration resulted in similar percentage weight loss (mean percentage of original weight + SEM) in diabetic (13.6 _+ 1.6%), glucose intolerant (16.4 _+ 3.3%) and obese nondiabetic (11.0+1.0%) subjects. Following therapy, plasma glucose concentrations 2 h after an oral glucose load declined in the diabetic (18.34_+ 0.81 to 10.67 _+ 0.50 mmol/l, mean _+ SEM; p<0.001) and in the glucose intolerant subjects (10.2 + 0.3 to 7.3 + 0.4 mmol/l, p < 0.01) while remaining unchanged in the obese non-diabetic subjects (7.09 + 0.23 to 6.77_+ 0.32 mmol/l, NS). Concentrations of total protein of plasma origin and albumin in 24-h urine collections were quantified by a sensitive immunonephelometric assay using specific antisera. Initially, 24-h excretion of total protein and albumin were elevated in the diabetic [rag protein/24 h; (median _+ 95% confidence limits): 63 (42-138), p<0.05; albumin : 26 (14-56), p < 0.05] and glucose intolerant subjects NS;, NS] compared with the non-diabetic subjects [protein: 20 (5-38); albumin: 6.2 (3.5-9.5)]. Following diet therapy, both total protein and albumin excretion were reduced significantly in diabetic subjects (p < 0.001) and similar decreases were observed in clearance rates of protein and albumin. Initially, 11 out of the 24 diabetic subjects had 24-h albumin excretion in the subclinical range (> 30, < 500 mg/24 h), whereas following diet therapy, only three out of the 11 had subclinical albuminuria. For all subjects, the decrease in albumin excretion following diet therapy was significantly correlated with the initial albumin excretion (r = 0.63, p < 0.0001). In one diabetic subject, whose glucose tolerance and albumin excretion were sequentially monitored for 14 months, the decreases in glycaemia and proteinuria observed in the first month of therapy persisted after discontinuation of diet therapy. Thus, metabolic control of Type 2 diabetes by a hypocaloric diet produced significant sustained reductions in proteinuria. The question remains whether or not this retards the development of clinical nephropathy or end stage renal disease.Key words: Type 2 diabetes, microvascular complications, proteinuria, albuminuria, hypocaloric diet.Throughout the last decade, evidence has accumulated to suggest that control of hyperglycaemia in man and animals may reverse or diminish the rate of progression of the microvascular complications of diabetes [1][2][3]. Definitive proof of this relationship has not been established. Major reasons for this failure may be that conventional methods of diabetic control do not achieve sustained normalization of hyperglycaemia [4][5][6], ...

The effects of rigorous insulin treatment on insulin action (insulin clamp) and secretion (plasma insulin response to glucose) were studied in 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Improvements were documented in fasting (P less than 0.0001) and postprandial (P less than 0.0001) plasma glucose concentrations, insulin secretion after oral glucose (P less than 0.001), and insulin action (P less than 0.005) after 30 days of therapy. Mean integrated plasma insulin response to glucose increased 2.5-fold after insulin therapy, but this improvement varied considerably from patient to patient. Insulin action also increased with insulin treatment and the resulting values were no longer significantly different from a weight- and age-matched group of subjects with normal glucose tolerance. However, there was considerable patient-to-patient variation in the degree to which insulin action was enhanced. The insulin-induced improvements in glucose tolerance persisted for at least 2 wk after insulin withdrawal, and were associated with continued increased insulin secretion and insulin action. In conclusion, control of hyperglycemia for 1 mo led to improvements in both insulin secretion and action in a series of obese patients with NIDDM that persisted for at least 2 wk after cessation of therapy.

Lipoprotein cholesterol and triglyceride concentrations were compared In diabetic and nondiabetlc Pima Indians, a homogeneous population with a high occurrence of noninsulin-dependent diabetes mellltus. Data were available on 690 subjects with diabetes or impaired glucose tolerance. Total and very low density lipoprotein (VLDL) triglycerides were approximately 150% of the nondiabetic values, but very few diabetics had pronounced hypertriglyceridemia. Significant elevations in low density lipoprotein (LDL) triglyceride were also observed In diabetic men and women of all ages. Decreases in high density lipoprotein (HDL) cholesterol were similar in diabetic men and women, and the differences in HDL cholesterol were much greater in less obese individuals. Changes In HDL in the diabetics were reflected in all three subfractions, HDLjb, HDL 2 ,, and HDL 3 . Both total and LDL cholesterol were elevated In diabetic women, but not In diabetic men. Thus, there were greater changes in lipoprotein distribution in diabetic women. When multiple regression analysis was performed to examine the relationships In diabetics between lipoproteins and other variables, plasma glucose appeared to be the variable most closely associated with plasma lipoproteins in diabetics (positive with VLDL and LDL, negative with HDL). In diabetics, obesity was correlated with HDL but not VLDL, whereas alcohol consumption appeared to be associated with VLDL but not HDL. (Arteriosclerosis 4:462-471, September/October 1984)