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A role for the increase in circulating norepinephrine (NE) during intense exercise [IE;or = 80% maximum O(2) uptake (VO(2max))] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 +/- 2 yr old; body mass index, 23 +/- 1 kg/m(2); VO(2max), 63 +/- 5 mL/kg.min) underwent 40 min of postabsorptive moderate-intensity (53% VO(2max)) cycle ergometer exercise (126 +/- 14 W), once without [control (CON)] and once with NE infusion (0.1 microg/kg.min) from 30-40 min (NE). With infusion, plasma NE reached 15.9 +/- 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 +/- 0.44 in CON, but rose to 7.55 +/- 0.68 mg/kg.min with NE infusion (P = 0.003). Ra correlated strongly (r(2) = 0.92, P0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 +/- 0.59 vs. 4.53 +/- 0.55 mg/kg.min, P0.02] and glucose metabolic clearance rate (P0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.

In intense exercise (80% maximum oxygen uptake) a huge, up to 8-fold increase in glucose production (Ra) is tightly correlated to marked increases in plasma norepinephrine (NE) and epinephrine. Both Ra and glucose uptake (Rd) are enhanced, not reduced, during beta-adrenergic blockade in normal subjects. Beta-blockade also caused a greater fall in immunoreactive insulin (IRI) during exercise, which could, in turn, have increased Ra directly or via an increased glucagon/insulin ratio. To control for adrenergic effects on endogenous insulin secretion, we tested type 1 diabetic subjects (DM) made euglycemic by overnight i.v. insulin that was kept constant in rate during and after exercise. Their responses to postabsorptive cycle ergometer exercise at 85-87% maximum oxygen uptake for approximately 14 min were compared to those of similar male control (CP) subjects. Six DM and seven CP subjects received i.v. 150 microg/kg propranolol over 20 min, then 80 microg/kg x min from -30 min, during exercise and for 60 min during recovery. Plasma glucose increased from similar resting values to peaks of 6.8 mmol/L in DM and 6.5 mmol/L in CP, then returned to resting values in CP within 20 min, but in DM, remained higher than in CP from 8-60 min (P = 0.049). Ra rose rapidly until exhaustion, to 13.3 mg/kg x min in CP and 11.6 in DM (P = NS). Ra declined rapidly in recovery, although somewhat more slowly in DM (P = 0.013 from 2-15 min). The Rd increased to 10.6 in CP and 9.2 mg/kg x min in DM (P = NS), then declined similarly in early recovery, but remained higher in CP from 50-100 min (P = 0.05). The rises in plasma glucose during exercise in both groups were thus due to the increments in Rd less than those in Ra. The higher recovery glucose in DM was due to the slower decline in Ra and the lower Rd in later recovery. IRI was higher in DM than in CP before exercise (P = 0.011), and whereas it decreased in CP (P0.05), it increased approximately 2-fold in DM, thus being higher throughout exercise (P = 0.003). The glucagon/insulin ratio was unchanged in DM, but increased in CP during exercise (P = 0.002). NE showed a rapid, marked increment during exercise to peak values of 23.7 nmol/L in CP and 25.7 nmol/L in DM (P = NS), and epinephrine showed parallel responses. Both correlated significantly with the Ra responses. In summary, the Ra responses of both DM and CP during exercise were greater than those of control unblocked subjects (previously reported) despite higher IRI (all exogenous) in DM. This suggests an important contribution of direct alpha-adrenergic stimulation to this Ra effect.

Oxygen free radicals have been shown to interfere with pancreatic islet beta cell function and integrity, and have been implicated in autoimmune type 1 diabetes. We hypothesized that the spontaneous autoimmune type 1 diabetes of the BB rat would be prevented by in vivo administration of a free-radical spin trap, alpha-phenyl-N-tert-butylnitrone (PBN). Twenty-eight diabetes-prone (BBdp) and 13 non-diabetes-prone (BBn) rats received PBN (10 mg/kg) subcutaneously twice daily, and 27 BBdp and 12 BBn rats received saline as controls. Rats were treated from age 47 +/- 6 days until diabetes onset or age 118 +/- 7 days. PBN caused no growth, biochemical, or hematological side effects. Sixteen control BBdp rats became diabetic (BBd, mean age 77 +/- 6 days) and six demonstrated impaired glucose tolerance (IGT rats). The incidence of diabetes and IGT was not different in PBN-treated BBdp rats. Saline-treated rats showed no differences in pancreatic malondialdehyde (MDA) contents of BBd, IGT rats, and the BBdp that did not develop diabetes, versus BBn rats (2.38 +/- 0.35 nmoL/g). Among rats receiving PBN, BBn had lower pancreatic MDA than BBd and IGT rats (1.38 +/- 0.15 vs. 1.88 +/- 0.15 and 2.02 +/- 0.24 nmoL/g, p0.05), but not than BBdp rats (1.78 +/- 0.12 nmoL/g, ns). BBn rats receiving PBN also had lower pancreatic MDA than the saline controls (p0.05). Thus, PBN is remarkably nontoxic and is able to decrease MDA in the absence of the autoimmune process, but does not prevent diabetes. A combination of PBN with other complementary antioxidant agents may hold better promise for disease prevention.

Clinical overlap between Cowden disease and Bannayan-Riley-Ruvalcaba syndrome has rarely been described and identical germline mutations in the PTEN gene have been demonstrated in a few families with Cowden disease and some cases of Bannayan-Riley-Ruvalcaba syndrome. We report on a mother with Cowden disease and a son with Bannayan-Riley-Ruvalcaba syndrome. Mutation analysis of the PTEN gene demonstrated a heterozygous nonsense mutation R130X in both individuals. This might suggest that Cowden disease and Bannayan-Riley-Ruvalcaba syndrome are one causal entity.

The autoimmune syndrome of the BB rat is associated with a marked increase in glutamine (Gln) metabolism in immune system cells of both diabetes-prone (BBdp) and diabetic (BBd) rats. To test whether inhibition of Gln metabolism prevents diabetes, 17 BBdp received acivicin (1 mg/kg) and 17 received saline subcutaneously every 2 days from age 48 days until diabetes onset or age 186 days. Twenty-seven non-diabetes-prone (BBn) rats served as controls. Acivicin caused some growth effects and a macrocytic anemia, but no other clinical or biochemical side effects. Only one acivicin-treated BBdp became diabetic (age 158 days), compared with saline-treated rats, of which 10 became diabetic and 2 became glucose intolerant (p0.001). Insulitis was moderate to severe in 88% of the saline-treated BBdp rats, but minimal in most acivicin-treated BBdp rats. Liver glutamine and glutamate tended to be higher in acivicin- than saline-treated BBdp rats. Acivicin caused no change in the proportions of T or B lymphocytes, NK cells, or macrophage phenotypes in spleen or blood; all BBdp rats were typically lymphopenic. Mitogenic responses of splenocytes in vitro were not affected. The results are consistent with the hypothesis that acivicin, by interfering with Gln metabolism, "targets" activated cells of the immune system and thereby attenuates the process and prevents overt diabetes, without major disturbance of Gln levels or generalized immunosuppression. This prevention is not due to a nutritional-growth retardation effect, as diabetes was prevented in females that showed no such effect.

To determine whether the kinetics of protein metabolism would differ with the prolonged use of a casein-soy 96 g protein, 1.7MJ/d very low energy diet (VLED) from those of a tryptophan- and methionine-supplemented hydrolyzed collagen VLED, in obesity.Clinical intervention study of 1 week isoenergetic diet followed by 6 weeks VLED.6 (1M,5F) healthy obese subjects (age: 38 +/- 4 y, BMI: 33 +/- 1 kg/m2, weight: 97 +/- 7 kg).Whole-body nitrogen (N) flux rate (Q) from 15N abundance in urinary urea using the oral 15N-glycine method and rates of protein synthesis (S) and breakdown (B) calculated from Q; N balance; resting metabolic rate; metabolic and hormonal responses.Q (per kg LBM) was maintained with both collagen and casein-soy VLED. S and B decreased (P0.05) at week 4 of both VLEDs with resulting decreases in net protein synthesis. At week 6, S decreased with both VLEDs, but B decreased only with casein-soy, at which time N balance was at equilibrium with casein-soy but returned to negative with collagen. Initial resting metabolic rate correlated with baseline Q and S. It decreased by 16% with the VLEDs; 25% of the decrease may derive from the decline in S.A 6 week casein-soy VLED with 46% of amino acids as essential does not provide a substantial advantage compared to hydrolyzed collagen with 16% of amino acids as essential. With prolonged use, it may better maintain N equilibrium by preventing further increments in protein breakdown.

To determine the changes in the plasma level of acylation stimulating protein (ASP) during a one month total fast in female subjects with marked obesity.Patients with marked obesity underwent a month total fast, before, during (2 weeks), and at the end of which, a variety of relevant metabolic parameters were measured.A metabolic unit of a teaching hospital.10 women with marked obesity were studied and the results compared with those in 16 age-matched controls.Plasma ASP, lipoprotein lipids, apoB, free fatty acid, and ketone levels.At baseline, fasting levels of ASP in the obese group were double that in control subjects (116 +/- 26 vs 53 +/- 30 nM P0.001). During the fast, ASP levels dropped progressively and were within the normal range at the end of the study (63 +/- 16 vs 53 +/- 30 nM pNS). In addition, there was a strong correlation between the plasma ASP at baseline before beginning the fast and the 4 week drop in ASP. That is, those subjects who had the highest starting ASP also had the largest 4 week drop in ASP (r2 = 0.644, P0.005). Of interest, as plasma ASP levels dropped, plasma free fatty acid and ketone levels rose and when all timepoints were considered, there was a significant inverse relation between plasma ASP and plasma free fatty acid (r2 = 0.295, P0.0002).The pattern of responses during the fast is that of increasing mobilization of fatty acids from adipose tissue coincident with decreased activity of the pathway responsible for the storage of adipocyte triglyceride mass. The data are consistent, therefore, with the role proposed for ASP as a major determinant of the rate of triglyceride synthesis in human adipocytes and thus a potentially important factor in the pathophysiology of obesity.

Because the dog can respond to a mixed-meal challenge with little or no change in plasma glucose concentration, we used kinetic techniques to quantify the magnitude and duration of changes in glucoregulation. Glucose turnover was measured using [3-3H]glucose and [U-14C]glucose over two 19-h periods in healthy dogs, first during a fast (n = 6) and then throughout the postprandial state (n = 6) after a single mixed meal. Mean arterial glycemia remained constant in the fasted state (7.5 +/- 0.2 mM) and in the fed state (7.6 +/- 0.3 mM). Glucose appearance (Ra), however, increased slowly after the meal from 38 +/- 2 mg/min to a maximum of 79 +/- 8 mg/min after 6 h and stayed elevated until 12 h (P < 0.001). In parallel, glucose disappearance (Rd) rose from 35 +/- 3 to 83 +/- 7 mg/min, closely matching the corresponding Ra. Glucose recycling rose from 25 +/- 8% at baseline to a maximum of 53 +/- 15% (P < 0.05) at 14 h in fed dogs, whereas levels for fasted dogs stayed between 19 +/- 7% at 0 h and 27 +/- 12% at 6 h. Insulin levels rose significantly 30 min after the meal from 67 +/- 7 pM to a peak of 208 +/- 54 pM at 6 h but remained elevated for 12 h. We conclude that 1) the dog was able to maintain postprandial glucoregulation by very precise matching of Ra and Rd such as to maintain glycemia constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Intense exercise to exhaustion is expected to be associated with rapid and large changes in glucose production (Ra) and utilization (Rd). To quantify these, and to determine their mechanisms and those of the prolonged postexercise hyperglycemia, we measured circulating metabolic regulators and glucose kinetics, the latter by the method of enriched tracer [3-3H] glucose infusion during exercise. Eighteen fit, lean young male subjects exercised to exhaustion at 80% of maximal workload (approximately 100% VO2max) on a cycle ergometer. Plasma glucose was 4.90 +/- 0.08 mM/L at rest, increased during exercise, then abruptly to 6.91 +/- 0.40 mM/L at 4 min recovery then gradually declined. Plasma insulin was constant during exercise, then doubled to 162 +/- 28 pmol/l until 20 min recovery, before declining. Plasma glucagon increased by 71 +/- 11 pg/mL. Plasma norepinephrine increased 18-fold and epinephrine 14-fold, both declining by 20 min recovery. Ra increased 7-fold by exhaustion to 13.0 +/- 1.18 mg/kg/min, then decreased to 2.43 +/- 0.24 mg/kg/min by 9 min, then to about 2 mg/kg/min the rest of recovery. Rd rose 3-fold (6.61 +/- 0.70 mg/kg/min), and remained lower than Ra to 7 min recovery, but thereafter declined more slowly. Thus, the rapid and extremely large increase in Ra was not matched by the increment in Rd during exercise and early recovery. We suggest that unlike in exercise of lesser intensity, the major mediators of both the increase in Ra and the restraint of the increase in Rd are the catecholamines. The post exercise hyperglycemia and hyperinsulinemia are appropriate to muscle glycogen repletion.

Changes in adipose tissue distribution as defined by the waist-to-hip ratio (WHR), were evaluated in 16 android, obese subjects (seven male and nine female) given a very low energy ketogenic diet of 1.72 MJ (411 kcal) for 4 weeks. Total weight loss was significantly greater for the males (11.2 +/- 2.5 kg) compared to females (8.3 +/- 0.8 kg); the relative weight loss however, was similar (9.9 vs 9.3 percent). Female and male losses in percent body fat and lean body mass were not significantly different. For both groups, significant (P less than 0.01) changes in waist and hip circumferences were observed; however, no significant changes were observed in WHR. These results indicate that in obese android male and female subjects, adipose tissue distribution as measured by WHR, does not change in response to rapid weight loss.

A longitudinal study of 51 weanlings from 5 litters of “BB” Wistar rats was undertaken to characterize the time course of the spontaneous diabetic syndrome. Nine rats developed overt diabetes. An abnormal glucose tolerance preceded the onset of the syndrome in 6 of these 9 rats. No other “clinical” or metabolic variable measured was predictive of the development of this syndrome. In these rats, the onset was remarkably abrupt, followed by rapid clinical deterioration with marked hyperglycaemia, glycosuria, ketonaemia and hypoinsulinaemia attained within 2 to 8 days. Pronounced insulitis was present in the early stages of the syndrome, resulting in complete B-cell destruction at the time of sacrifice at 7 to 40 days. Among the 42 littermates, 9 revealed sequential abnormalities in oral glucose tolerance tests performed at weekly intervals (to age 90–120 d) though remaining aglycosuric and maintaining normal fasting plasma glucose levels. In 7 of these rats, a milder form of the same islet inflammatory lesion seen in the overtly diabetic animals was present. Thus the new features identified are: 1) a time course of evolution from normoglycaemia to overt diabetes telescoped into a period of days, and 2) a “chemical” stage or form with an insulitis similar to that found in the early stages of overt diabetes.

Glucose was infused into anaesthetized dogs before and after pancreatectomy. In the diabetics blood glucose was regulated first by closed-loop and then by open-loop insulin delivery schemes. Insulin requirements for the latter were determined by resolving the former into a sequence of 3 different infusion rates: during the baseline and recovery periods, basal insulin was delivered at 0.37 +/- 0.02 mU/kg/min, while during the 60 min glucose infusion (10 mg/kg/min) there was an 8 min infusion at 4.96 +/- 0.37 mU/kg/min and a 52 min component at 1.85 +/- 0.08 mU/kg/min. With the open-loop method under these highly standardized conditions glycaemia was similar to normal controls but IRI levels were significantly higher, 13.5 vs 8.0 microU/ml (p less than 0.05) in the baseline and recovery periods and 74 vs 25 microU/ml (p less than 0.05) during the glucose infusion. It was concluded that: constant normoglycaemia can be maintained in the basal state by a constant rate of peripheral insulin delivery but at rates resulting in peripheral hyperinsulinaemia; the glycaemic response to glucose infusion can be normalized by a two component waveform of insulin delivery; and the closed-loop method can serve as a useful guide in determining insulin requirements.

To test for a possible role of adrenergic mechanisms in the altered glucagon secretion in the spontaneously diabetic "BB" rat, the responses of glucose, insulin, and glucagon to adrenergic blocking agents in diabetic and normal rats were compared at rest and during 2 h of immobilization stress. In unstressed normal rats, phentolamine alone caused a 20 mg/dl fall in glycemia, 1.2 ng/ml rise in insulin (IRI), and no change in glucagon (IRG), whereas the only effect of propranolol was a minor rise in glycemia. Stress caused increments in glycemia of 72 mg/dl and in IRG of 94 pg/ml, and no change in IRI. Phentolamine significantly attenuated the stress-related increments, and IRI increased by the same amount as in the unstressed state. Propranolol exhibited no statistically significant effects on the response to stress. These findings are consistent with alpha-adrenergic stimulation of IRG and suppression of IRI secretion. In unstressed diabetic rats (mean time 0 glycemia, 431 mg/dl), propranolol caused only a small rise in glycemia, whereas phentolamine induced marked increments of glycemia (131 mg/dl) and IRG (116 pg/ml). Stress alone did likewise (189 mg/dl, 122 pg/ml) as did stress with the phentolamine (271 mg/dl, 144 pg/ml). However propranolol significantly attenuated the stress-induced increments in glycemia (88 mg/dl) and IRG (82 pg/ml). Thus both alpha- and beta-adrenergic receptors influence IRG secretion in the diabetic rats. An in vivo model for elucidating neural control of glucoregulation has been developed that is independent of cardiovascular fitness.

A white female, now age 40 and receiving total parenteral nutrition for more than 5 years, developed unexpected 15% weight loss after 3 1/2 years of regimen, together with peripheral neuropathy confirmed by nerve conduction measurements. An intravenous glucose tolerance test showed that the fractional rate (K) had decreased to 0.89%/min (normal greater than 1.2). There was observed during this glucose infusion a borderline normal insulin response with a fall in plasma free fatty acids and in plasma leucine. During daily infusion of well over 400 g of glucose, the respiratory quotient was 0.66. Chromium balance was negative. Chromium levels were, in blood 0.55 ng/ml (normal 4.9 to 9.5) and in hair 154 to 175 ng/g (normal greater than 500). Regular insulin daily (45 micron) in the infusate nearly maintained euglycemia but despite this, and even with further glucose intake to restore weight loss, intravenous glucose tolerance test (K) and respiratory quotient were unchanged. Administration of insulin was then stopped and 250 microng of Cr added to the daily total parenteral nutrition infusate for 2 weeks. After this the intravenous glucose tolerance test (K) and respiratory quotient became normal (1.35 and 0.78, respectively). Over the next 5 months insulin was not needed and glucose intake had to be reduced substantially to avoid overweight. In this period nerve conduction and well-being returned to normal. With a maintenance addition of chromium to the total parenteral nutrition infusate (tentatively this addition is 20 microng/day) the patient has remained well for 18 months (to July 1976). These results suggest that relatively isolated chromium deficiency in man, hitherto poorly documented, causes 1) glucose intolerance, 2) inability to utilize glucose for energy, 3) neuropathy with normal insulin levels, 4) high free fatty acid levels and low respiratory quotient and, 5) abnormalities of nitrogen metabolism.

The metabolism of endogenous and exogenous amino acids has been characterized during a 16-h fast after birth in the rat. Eighteen of 22 amino acids showed a decrease in plasma concentration up to 16 h, the most profound and sustained changes affecting those quantitatively important in gluconeogenesis. The hepatic accumulation of injected [14C]aminoisobutyric acid showed a progressive rise after birth. The in vivo conversion of 14C-labeled lactate, alanine, serine, and glutamine to [14C]glucose increased for 6 h, but all except glutamine showed a decline by 16 h. The in vitro conversion of several gluconeogenic substrates (10mM), however, increased with time in each instance. These data confirm that the capacity for hepatic gluconeogenesis and maintenance of blood glucose concentration appears immediately after birth. Nevertheless, profound hypoglycemia recurs at 16 h and responds only minimally and transiently to exogenous gluconeogenic substrate loads. In contrast, the fed newborn maintains normoglycemia, higher endogenous amino acid levels, and the capacity for substrate conversion at this time. The mechanism for stimulation of hepatic gluconeogenic pathways thus is present in both fasted and fed neonatal rats. However, owing to insufficient energy sources to sustain gluconeogenesis and to inadequate gluconeogenic substrate, the rat is unable to maintain normoglycemia if fasted 16 h.

The BB rat develops a spontaneous type I diabetic syndrome with anti-islet autoimmunity. Sera from diabetic and nondiabetic BB rats (from diabetes-prone litters), nondiabetic BB rats (from low-risk lines), and nondiabetes-prone Sprague-Dawley rats were collected twice a week from age 40 days to 160 days. Sera were tested for: (1) complement-dependent toxicity to 51Crlabeled islet cells in vitro; (2) immunoglobulin binding to RIN-5 F insulinoma cells; and (3) ability to selectively suppress insulin secretion from normal islets in vitro. All sera from rats that subsequently became diabetic or glucose-intolerant were toxic to islet cells from various rat strains in the presence of complement. They were toxic neither to hepatocytes nor to fibroblasts. The toxic potency was associated with the globulin fraction. It was, in most cases, maximal either before or immediately after the onset of the disease. Sera from the nondiabetes-susceptible BB rats and the rats which, in diabetes-prone litters, died too early to be classified tended toward greater toxicity to islets. Immunoglobulins from diabetic sera bound to RIN-5 F cells more than did the serum globulins from other groups, their maximal binding capacity occurring afterthe onset of diabetes. Furthermore, BB diabetic sera were capable of selectively inhibiting the insulin secretion from normal rat islets in vitro either in the presence or, in some cases, in theabsence of complement. The A- and D-cell functions were not suppressed. The combination of such results suggests the presence of one or more antibodies capable of binding to beta cells, inhibiting their function, and inducing their lysis. These antibodies may contribute to the beta cell disruption in this model of diabetes.

A longitudinal study of thirteen rats with transient and intermittent episodes of glycosuria was undertaken, to further characterize the "BB" diabetic syndrome. "Chemical diabetes" (normal fasting glycemia, abnormal GTT) was observed in five rats, accompanied by the same dramatic insulitis previously reported in this syndrome, in two of the three pancreases examined. Progression from "chemical" to overt diabetes occurred in one of these rats. Two other patterns of presentation were observed. Periods of complete remission occurred in four rats with diabetes considered sufficiently severe to warrant previous treatment with insulin. Four additional rats with previous glycosuria (untreated) showed no abnormalities on followup. It is not known whether hyperglycemia accompanied the glycosuria in these rats, and renal glycosuria has not been excluded. Thus, the "BB" diabetic syndrome exists in not only the overt and "chemical" forms, but may also present with transient glycosuria, followed by a variety of subsequent progressions.

The urinary excretion of 3-methylhistidine is used as a convenient index of muscle protein catabolism. Histidine is methylated in peptide linkage within muscle protein, and is quantitatively excreted when the protein is catabolized. 3-Methylhistidine would be expected to be present in ingested muscle protein, and unless altered in the digestive process, to be excreted as a function of intake. We studied its excretion at four levels of mixed protein intake, in separate groups of obese subjects, on the 1st day of altered input, with and without concurrent energy provision. A significant (P less than 0.001) linear relationship between protein intake and 3-methylhistidine excretion was observed, with a mean excretion of 198 mumoles/day at 0 intake, and an increment of 1.34 mumoles/g of ingested protein. There was no relationship between its excretion and the concurrent nitrogen balance. Thus, estimates of muscle protein catabolism with this method require that muscle protein be absent from the diet or its contribution quantified.

BB rats of diabetes-prone lines develop a spontaneous Type 1 diabetic syndrome, with many immunological concomitants. No data are available as to the integrity of their islet beta cells prior to onset of the insulitis which proceeds to their selective destruction. We tested the effects of the beta-cytotoxins streptozotocin and alloxan on such rats, compared to Wistar and to non diabetes-prone BB control rats studied prior to usual age of diabetes onset. A dose-response of a single injection of the agents with respect to pancreatic insulin content 48 hr post-injection as well as to circulating insulin and glucose, weight, and lymphocyte counts was established. Clear dose-responses were found for pancreatic insulin content. Though less sensitive, plasma insulin and glucose values showed responses. Whereas some litters of diabetes-prone rats showed greater reductions of pancreatic insulin than controls after some doses of streptozotocin, overall results in 8-26 recipients of each dose showed no significant differences when compared with either BB or Wistar controls. With smaller numbers of diabetes-prone rats, the same was obtained for alloxan, though with fewer doses tested. The latter required the construction of an alloxan dose-response in normal Wistar rats. Thus, this study has not demonstrated a nonspecific increase in "fragility" of BB rat beta cells in response to these classical diabetogenic agents. This would be consistent with other data suggesting that the primary abnormality in the syndrome does not necessarily reside within the beta cell.

An improved bedside technique for the continuous monitoring of glycemia is described. A linear relationship results between whole blood glucose concentration and plasma glucose levels, and allows the calibration of the system in terms of plasma glucose levels. In operation venous blood is withdrawn at a steady rate using a double-lumen catheter and directed to a continuous-flow laboratory analyzer, where glucose analysis is carried out using a modified glucose oxidase-peroxidase methodology. The improvements in this technique include: i) a reduction in the delay of the analyzer to 90 s, making it suitable for application in a system for blood glucose regulation, ii) a minimal blood requirement of 3 ml/h, permitting long-term monitoring, iii) elimination of the need for systemic anticoagulation, iv) an excellent correlation (r = 0.993) between the measured whole blood glucose and the actual plasma glucose concentration, v) an average baseline drift of +0.5 mg%/h, vi) a sensitivity loss of less than 0.1%/h, and vii) a reasonable operating cost. This technique was implemented as part of a clinical apparatus known as an artificial endocrine pancreas which has been reliably applied in clinical and animal studies.

In an attempt to minimize fluid retention and obtain a gradual return to the pre-fast metabolic state, 14 nondiabetic obese subjects, who had fasted totally for 32 +/- 3 days, were fed a hypocaloric diet that incorporated stepwise increments in carbohydrate beginning at 20 g/day. During the refeeding period of 14 days, the total caloric intake for the first 9 days was 800 kcal/day and 1000 kcal/day thereafter. No untoward clinical events occurred. A weight regain of 2.2 +/- 0.4 kg during the first 7 days was accounted for by fluid retention. The return to pre-fast postabsorptive plasma glucose levels (82 +/- 3 to 93 +/- 3 mg dl-1) and a rise in immunoreactive insulin (0.5 +/- 0.1 to 0.8 +/- 0.1 ng ml-1) occurred by day 7. Blood 3-hydroxybutyrate and acetoacetate concentrations (4.1 and 0.6 mM, respectively) declined more slowly to reach pre-fast values by day 14; urinary excretion of 3-hydroxybutyrate dropped from 64 mmol/day to pre-fast levels by day 10. Urinary nitrogen excretion increased from 2.6 to a plateau of 5.5-6.0 g/day from day 3 onward; nitrogen balance was at least +3 g/day throughout refeeding. This approach to refeeding is associated with acceptable clinical response and may be appropriate after other states of marked caloric deprivation.

A case of gyrate atrophy of the choroid and retina associated with hyperornithinemia has been subjected to extensive clinical and biochemical investigation. The familial occurrence of the ocular disease and of abnormality of amino acid was unique to this 28-year-old male, being absent in parents and siblings. He presented with progressive visual loss, and was found to have cataracts and large areas of peripheral lacunar atrophy. Clinically there was no other abnormality. However, he was hyperuricemic and has an abnormal EEG. Despite otherwise normal biochemical indices of hepatic, renal, and muscle function; selective catheterization of an artery, the hepatic vein, the renal vein, and a deep forearm vein showed all of these circulatory beds to be producing ornithine according to arteriovenous difference measurements. Cerebrospinal fluid and urine contained increased amounts of ornithine. Though electromyography was normal, the muscle biopsy was abnormal. Clinical tests including arginine loading, glucose tolerance testing, and other measurements of blood variables provided inferences as to the metabolic locus of the abnormality. The syndrome is a systemic multiorgan disorder in which the choroid and retina would appear to be target organs and the hyperornithinemia to be of, as yet, undetermined cause and pathogenic significance.

The relationships between changes in the plasma levels of immunoreactive insulin (IRI) and glucagon (IRG) in response to the postprandial increments of circulating amino acids were studied under normal physiological conditions in healthy dogs. In the presence of a unique postprandial physiological euglycemic "glucose clamp" which occurs in these dogs, plasma IRG rose to an earlier peak than IRI and both remained elevated for 16-19 hr. Amino acid (AA) profiles also showed postprandial incremental responses for up to 16 hr. Multiple correlation analyses indicated that only branched chain AAs were significantly correlated with IRI profiles and were devoid of a relationship to IRG. Similarly, only ornithine, lysine and glycine were significantly correlated with IRG profiles and devoid of a relationship to IRI. The significance of individual IRG stimulating effects of alanine and arginine were masked by other amino acid interactions, as significant intercorrelation was found among all 13 amino acids. Two equations were derived from the multiple regression analysis accounting for the postprandial time course of changes in IRI and IRG levels with only 5 amino acid concentrations: (1) (delta IRI) = 0.37 (delta Leu) -0.45(delta His), and (2) (delta IRG) = 0.55(delta Orn) + 0.37(delta Gly) -0.69 (delta Ser). These observations confirm the physiologic role in islet hormone secretion of the postprandial increments in circulating amino acids in the absence of glycemic change.

A glycaemic control identical with the normal has been achieved in unrestrained totally depancreatised dogs using a portable open-loop insulin delivery system. The device consisted of a battery power pack with a flow-rate controller, an insulin reservoir and a peristaltic pump from which pulses of insulin were delivered every 90 seconds into the inferior vena cava through an exteriorised indwelling catheter. Insulin was infused at the basal rate of 0.45±0.03 mUkg−1 min−1 (Mean±s.e.m.) in the postabsorptive state resulting in peripheral IRI and plasma glucose levels of 12±1 μU ml−1 and 86±7 mg dl−1. In the postprandial period the infusion rate was enhanced sevenfold to the rate of 3.16±0.21 mU kg−1min−1 for 7h and then reduced to 1.05±0.07 mU kg−1 min−1 for an additional 2.25 h. A weight-maintaining constant diet was provided and the resulting glycaemic profiles were similar to age, sex and weight-matched healthy controls. Fasting peripheral insulin levels in the infused diabetic dogs were not significantly different from non-diabetic controls (10±1μUml−1). However, in the postprandial period of enhanced delivery, insulin levels in the diabetic dogs were 3.1 times higher than the controls. With the compound square waveforms of preprogrammed insulin infusion found appropriate in this study unaccountable low or high plasma glucose levels did not occur but hyperinsulinism accompanied the glycaemic normalisation following a mixed meal.

Many individual factors have been related to development of proliferative diabetic retinopathy. To evaluate possible interactions among these, a constellation of variables were studied in 22 patients with long duration of insulin-dependent diabetes mellitus for greater than 25 years, with minimal background diabetic retinopathy, and compared to 27 patients with insulin-dependent diabetes mellitus for a variable duration, but with bilateral proliferative retinopathy. The patients were compatible in age at onset of diabetes (12 +/- 2 in proliferative retinopathy group vs 12 +/- 1 yr in the background retinopathy group). Following initial standard statistical analyses, data were further analysed using Logistic Regression Analysis. In the proliferative retinopathy group males were more prevalent (2.9:1), and patients were treated with larger insulin doses (0.86 +/- 0.07 vs 0.59 +/- 0.04 U/Kg B.W., p less than 0.001). Systemic hypertension and neuropathy were more prevalent (p less than 0.02 and less than 0.004 respectively), and diastolic blood pressure was higher (87 +/- 3 vs 75 +/- 2, p less than 0.01). In the same group diet was higher in carbohydrate and the ratio of polyunsaturated to saturated fats was lower (p less than 0.03, less than 0.05 respectively). HbA1 was higher (0.127 +/- 0.004 vs 0.110 +/- 0.004%, p less than 0.004), but the mean of all available plasma glucose values was not different. Impaired renal function expressed by higher BUN, serum creatinine, and urinary protein and lower creatinine clearance was observed. Nerve conduction parameters were more significantly impaired and plasma triglycerides were higher (1.74 +/- 0.2 vs 0.85 +/- 0.1 mmol/l, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in energy metabolism, substrate use, and hormone profiles were prospectively studied in 31 patients with small cell lung cancer receiving chemotherapy. Patients were randomized to receive either 4 weeks of total parenteral nutrition (n = 15) or to continue self-regulated p.o. diet (control group; n = 16). The initial actual resting energy expenditure measured by indirect calorimetry was 31% higher than the predicted resting energy expenditure determined by the Harris-Benedict formula. The p.o. calorie intake was inappropriately low for these hypermetabolic patients. Total parenteral nutrition resulted in a significant positive net energy balance, but in follow-up was associated with prolonged anorexia and a negative energy balance. Complete response to therapy reduced resting energy expenditure and increased calorie intake, whereas the contrary was true in nonresponders. Elevated plasma-free fatty acids (800 +/- 62 microM; S.E.) and a low respiratory quotient (0.74 +/- 0.02) indicate that the dominant energy source in patients with small cell lung cancer is fat, and that increased fat oxidation continues despite tumor response. Elevated fasting plasma catecholamines and insulin resistance may contribute to continued fat mobilization. Initially, there was a significant increase in blood lactate (1118 +/- 95 microM) suggesting either increased tumor or tumor-mediated glycolytic activity. Response to therapy was associated with a fall in blood lactate levels. The most effective way of improving the metabolic derangements in patients with small cell lung cancer was to achieve tumor response to therapy.

A new, spontaneously diabetic syndrome has been recognized in nonobese outbred Wistar rats of both sexes. The age at detection of first glycosuria has varied from 48 to 120 days, with a mean of 67 days. Eighteen rats have been studied, 14 untreated and four during and after cessation of insulin treatment. The affected animals have demonstrated a spectrum of severity, with hyperglycemia (252–732 mg./dl.), hypoinsulinemia (0–1 ng./ml.), and hyperketonemia. The severely ketotic rats, with total blood ketone body levels between 6 and 13 mM, showed rapid loss in weight and dehydration over one to six days. The moderately ketotic (1–5 mM) declined gradually in weight over 15 days, with marked polyuria and glycosuria. The stable rats, with ketonemia less than 1 mM, sustained their weights, polyuria, and glycosuria for longer than 40 days. A relative or absolute increase in plasma immunoreactive glucagon and elevated levels of free fatty acids and branched-chain amino acids were observed in relation to the severity of the syndrome. Intraperitoneal arginine or tolbutamide elicited no insulin response, but the glucagon response to arginine was exaggerated. Pancreatic insulin content was markedly diminished and glucagon content was normal or moderately decreased. Light-microscopic examination of pancreases of ketotic animals at the end stage of the disease showed islets to be very small and rare, consisting virtually of non-β cells. In stable and earlier ketotic rats, the islets were small, with reduction in β-cell number and a striking inflammatory cell infiltration. Surviving β cells showed variable degranulation. This model of spontaneous diabetes in nonobese rats displays insulin deficiency, glucagon excess, and ketosis, with a dramatic inflammatory lesion during active β-cell destruction.

The alleged benefits of protein diets remain unproven, since research data on the safety and long-term utility of protein products as the principal or only source of nutrients for weight reduction programs are as yet insufficient. First, it is uncertain whether the decreases in body protein turnover occurring with these diets are consistent with normal function over long periods, though net balance of protein is obtained. Second, the main advantage to the patient is the suppression of appetite by the ketoacidosis, but it is the ketoacidosis that causes many of the untoward effects. Third, the addition of carbohydrate to a protein diet does not mitigate the benefit of the protein and prevents most of the untoward effects. Fourth, there is clearly no advantage of "predigested" proteins (which are generally poorer in quality than normal high-protein foods) except for the psychologic factor of being given "medication" for the "disease" of obesity. Fifth, there is a distinct danger of deficiencies of micronutrients developing with prolonged consumption of unsupplemented diets. Sixth, the cardiac disorders associated with death in persons taking these diets have not been shown to be coincidental rather than a direct consequence of the diets.In the present state of understanding of protein diets, they should be supervised only by specially trained physicians in rigorous multidisciplinary programs, preferably those with ongoing research. Only individuals free from contraindications should be so treated. Until compelling data proving the safety and efficacy of these diets are forthcoming, the general public should be counselled against their use.