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Lipid and carbohydrate homeostasis in higher organisms is under the control of an integrated system that has the capacity to rapidly respond to metabolic changes. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. The three PPAR subtypes, , , and , have distinct expression patterns and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. Recent advances in identifying selective ligands in conjunction with microarray analyses and gene targeting studies have helped delineate the subtype-specific functions and the therapeutic potential of these receptors. PPAR potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates (e.g. fenofibrate and gemfibrozil), whereas PPAR is essential for adipocyte differentiation and mediates the activity of the insulin-sensitizing thiazolidinediones (e.g. rosiglitazone and pioglitazone). Recent evidence suggests that PPAR may be important in controlling triglyceride levels by sensing very low-density lipoprotein. Thus, uncovering the regulatory mechanisms and transcriptional targets of the PPARs will continue to provide insight into the pathogenesis of metabolic diseases and, at the same time, offer valuable information for rational drug design. (Endocrinology 144: 2201–2207, 2003)

Publisher Summary The disturbances of carbohydrate homeostasis have interested clinicians and scientists since the recognition of diabetes mellitus. A parallel line of study emerged in the study of patients with recurrent or chronic hypoglycemic syndromes. These studies eventually led to an understanding of fuel-hormonal interrelationships with insulin playing a prominent role. However, this understanding has remained quite incomplete even following the discovery of several gene families that influence carbohydrate homeostasis. These families include the active co-transporters (SGLTs) and the facilitative glucose transporters (GLUTs). The recognition of these two gene families has expanded our understanding of carbohydrate metabolism and introduced new insights into human disease states. Now it is understood that the molecular basis for old conditions, such as the Fanconi-Bickel syndrome, and newer conditions such as the glucose-galactose malabsorption syndrome and the GLUT1 deficiency syndrome. However, understanding of disturbed carbohydrate homeostasis in the setting of diabetes mellitus remains incomplete, and it is expected that there will be further insight into the pathogenesis of this common human condition as we continue to explore the factors that control the movement of glucose across tissue membranes. This chapter focuses on the several clinical conditions that have been associated with documented mutations affecting the two glucose transporter gene families.

MitoNEET is an outer mitochondrial membrane protein that, upon overexpression in white adipose tissue (WAT), exerts a positive impact on tissue expansion and whole-body lipid and carbohydrate homeostasis by altering mitochondrial matrix iron metabolism. Here we determine the key transcriptional events in subcutaneous WAT of mice in response to mitoNEET overexpression and a high-fat diet (HFD). Microarray analyses at key points during weight gain upon body weight divergence with wild-type mice demonstrate that mitoNEET-enriched sWAT early on, upregulates a browning signature programme that limits WAT expansion in transgenic mice for a period of up to 12 weeks of HFD. This compensatory browning phenotype is subsequently lost, resulting in rapid WAT expansion and body weight gain. Exposure to thermoneutral temperatures during HFD prompts weight gain significantly earlier. Similar WAT expansion is achieved upon infection with an adeno-associated virus expressing mitoNEET. Collectively, the mitoNEET-enriched fat pads feature a more vascularized, anti-inflammatory and less fibrotic environment.

The stability of the function of the reproductive system depends on a multitude of factors of the internal and external milieux. Serious disturbances in its function, with alterations in carbohydrate homeostasis, underlie such diseases as diabetes mellitus. Disturbances to the functional activity of the reproductive system in laboratory animals with diabetes are known to be associated not only with destructive changes in the gonads, but also with dysfunction of the hypothalamo-hypophyseal complex [9, 11]. Published data show that these lesions have different severities in male and female individuals [7, 8]. The question of the extent to which lesions due to the diabetic state depend on the level of sex steroids and insulin in the body thus far remains unanswered. Unlike the situation in males, females are characterized by cyclic changes in the activity of the reproductive system. Thus, it is possible that differences in the regulation of gonadotropic function in male and female rats, observed in normal animals, could explain their different sensitivities to diabetes. Thus, we elected to carry out various studies of the functional activity of the hypothalamo-hypophyseal-gonadal system in male and female rats with experimental diabetes induced by administration of streptozotocin (STZ).

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor (FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.

Pregnancy is considered diabetogenic. Although exercise has been advocated to assist in metabolic control of the nonpregnant diabetic individual, there is a paucity of data about the metabolic effects of exercise during pregnancy. To examine whether moderate exertion may be beneficial in the maintenance of maternal carbohydrate homeostasis, glucose and lactate kinetics were measured in the third trimester in five pregnant nondiabetic women (gestational age, 34.2 +/- 0.1 weeks [mean +/- SE]) by infusion of 45 microg x kg(-1) x min(-1) [6,6-2H2]glucose and 70 microg x kg(-1) x min(-1) [U-13C]lactate tracers. Subjects were observed at rest for determination of baseline steady-state kinetics over a 30-minute period, and then they exercised for 30 minutes at 60% maximum oxygen consumption (VO2max) and were evaluated for 30 minutes postexercise. Glucose and lactate kinetics and lactate oxidation were measured throughout the exercise protocol. This study was repeated postpartum in all individuals at least 6 weeks after delivery. Compared with the steady-state preinfusion period, plasma glucose concentration was not elevated during exercise in either group, nor was plasma lactate concentration significantly different in either group. Glucose kinetics did not change during exercise, but lactate kinetics increased in both groups. V02 and percent of lactate C contribution to CO2, an indication of lactate oxidation, increased proportionally in both groups during exercise. Metabolic perturbations, as measured by glucose and lactate kinetics, do not appear to be different during the third trimester of pregnancy during a relatively short bout of exercise compared with the nonpregnant state.

Hyperparathyroidism is associated with impaired glucose tolerance, and parathyroidectomy may improve carbohydrate homeostasis. It has been suggested that parathyroid hormone (PTH) suppresses insulin secretion but it is unclear whether it also interferes with the peripheral action of insulin. To evaluate in vivo effects of PTH on insulinmediated glucose utilization, 15 male Sprague Dawley rats were continuously infused with rat PTH (1–34) using an Alzet miniosmotic pump at a rate of 0.03 nm/hour. Controls were infused with the vehicle alone. Following 5 days of PTH infusion, plasma calcium (Ca) levels were higher in the PTH-infused rats (12.3±0.2 versus 9.9±0.1 mg/dl, P

We have previously reported that in rats 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality is associated (although not necessarily causally) with changes in brain serotonin (5-HT) metabolism. In the present study, we have examined whether this holds for other species by comparing the effect of TCDD in the most TCDD-susceptible and the most TCDD-resistant species, guinea pigs and hamsters, respectively. Body weight gain of guinea pigs exposed to TCDD (0.3-2.7 micrograms/kg) diminished dose dependently, while the effect was marginal in hamsters (900-4600 micrograms/kg). Brain 5-hydroxyindoleacetic acid (the main metabolite of brain 5-HT), brain tryptophan (the precursor amino acid of 5-HT), and plasma free and total tryptophan were not affected at any dose in guinea pigs. In contrast, 4 days after exposure, the levels of plasma free and total tryptophan were consistently increased in hamsters. These, as well as brain tryptophan, were still elevated 10 days after exposure. TCDD did not affect plasma glucose level in either species. Liver glycogen was decreased in a dose-dependent manner in TCDD-treated guinea pigs as well as in their pair-fed controls on day 10. There was no change in liver glycogen in hamsters. The activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase was only depressed in hamsters by all doses of TCDD. We conclude that changes in tryptophan metabolism or in carbohydrate homeostasis cannot explain the wide interspecies differences in susceptibility to the acute lethality of TCDD, although they may correlate with some aspects of its toxicity in certain species.

Publisher Summary Carbohydrates are key to the metabolism of all vertebrates, including fish species. The diversity of lifestyles and habitats selected by fish has resulted in significant differences in the way species handle and partition dietary carbohydrates within their bodies. The red blood cell and kidney cortex of mammals have a strict glucose requirement based upon their anaerobic metabolic profile. Fish red cells are nucleated and may contain a few mitochondria and it is reported that 90% of the resting nucleoside triphosphate is produced aerobically. This chapter provides an overview of recent studies on carbohydrate metabolism in fish using a tissue approach. An overriding thesis in the chapter is that carbohydrate metabolism has a significant role in fish and that this function becomes more understandable when considered in the light of the perturbations of the system. The question of whole fish carbohydrate homeostasis is examined in the chapter only in terms of its importance to the individual tissue. It discusses the general organization of hepatic metabolism and the signal transduction pathways of hormones. . The organization of kidney metabolism is also elaborated in the chapter.

Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals. During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of antiinflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines. This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human. Keywords: Ghowth hormone; obesity; inflammation; calorie restriction; aging (Published: 4 April 2012) Citation: Pathobiology of Aging & Age-related Diseases 2012, 2 : 17293 - DOI: 10.3402/pba.v2i0.17293

The influence of hyperinsulinemic-hyperglycemia on protein and carbohydrate homeostasis was assessed using L-[1-13C]-leucine and [3-3H]glucose combined with open-circuit indirect calorimetry. After a 30-min basal period, healthy human volunteers were subjected to two sequential experimental periods (150 min each) during which insulin was continuously infused at a rate to elicit maximal effects (10.0 mU.kg-1 x min-1, resulting in 220-fold basal levels) in conjunction with an infusion of L-amino acids to maintain euleucinemia. Plasma glucose was maintained near basal (94 +/- 2 mg/dl) during period I and at twofold basal (191 +/- 4 mg/dl) during period II. The endogenous rate of leucine appearance (index of proteolysis in mumol.kg-1 x h-1) dropped by 80% from basal during period I (P < 0.01) but only by 44% during period II. Although hyperglycemia stimulated the rate of proteolysis threefold (18.0 +/- 10.2 to 49.8 +/- 7.2, P < 0.001), neither leucine oxidation nor nonoxidative leucine rate of disappearance (an estimate of protein synthesis) was altered. During both glycemic conditions, the rates of hepatic glucose production were completely suppressed, and this was accompanied by 3- and 11-fold increases in the estimated rates of protein and carbohydrate oxidation, respectively, and an 80% decrease in the rate of lipid oxidation. The estimated rate of glucose storage was increased fourfold during period I and by an additional 2.3-fold (to approximately 10-fold basal) in period II. The present study demonstrates that, during hyperinsulinemia, acute elevations of plasma glucose to two times basal levels result in a marked stimulation of whole body proteolysis during hyperinsulinemia.

Rat liver is known to contain both a nitric oxide-stimulated guanylate cyclase and a cGMP-stimulated cAMP-phosphodiesterase. To evaluate the possible function of this system, the effect of the nitric oxide generating compound S-nitroso-N-acetylpenicillamine on glycogenolysis was evaluated in isolated rat hepatocytes. S-nitroso-N-acetylpenicillamine (1.0 mM) inhibited glucagon-stimulated glycogenolysis by 15%, but had no effect on basal rates of glycogenolysis. Inhibition of hepatocyte glycogenolysis by S-nitroso-N-acetylpenicillamine was associated with accumulation of cGMP (1.5 pmol/2.0 × 106 cells/2 min.). Exogenous 8-Br-cGMP (1.0 mM) inhibited hepatocyte glucagon-stimulated glycogenolysis by a magnitude similar to that observed with S-nitroso-N-acetylpenicillamine. S-nitroso-N-acetylpenicillamine had no effect on phenylephrine-stimulated glycogenolysis, but inhibited 8-bromo-cAMP-stimulated glycogenolysis by 15%. These observations suggest that S-nitroso-N-acetylpenicillamine inhibits cAMP-mediated stimulation of glycogenolysis at a site distal to adenylate cyclase. In summary, hepatocyte glucagon-stimulated glycogenolysis was inhibited to a small, but significant, degree by S-nitroso-N-acetylpenicillamine. This inhibition is consistent with a nitric oxide mediated stimulation of guanylate cyclase and consequent stimulation of cAMP-phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiologic conditions.

Sepsis hyperglycemia is poorly understood. It is not known whether there is a role in sepsis hyperglycemia for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), crucial for normal glucose metabolism. We developed an in vitro model of sepsis employing monocytes (crucial cells in mediating sepsis) and hepatocytes (crucial cells in carbohydrate homeostasis) to clarify the role of the incretin system in sepsis.

Predictable and well-recognized physiologic and metabolic alterations occur in response to trauma, sepsis or surgery. The major posttraumatic effects are: increased metabolic rate, protein breakdown, negative nitrogen balance, and alteration of the carbohydrate homeostasis, including elevated blood glucose concentration, increased endogenous glucose production, elevated insulin levels and insulin resistance.

The fetus is completely dependent on mother for glucose and other nutrient transfer across the placenta. At birth, when the maternal supply is discontinued, the neonate must adjust to an independent existence. The changes in the neonate's glucose homeostasis during this transition to the extrauterine environment are influenced by the mother's metabolism and intrinsic fetal and placental problems. Maturation of carbohydrate homeostasis results from a balance between substrate availability and coordination of developing hormonal, enzymatic, and neural systems. These mechanisms may not be fully developed in neonates, so the neonate is vulnerable to carbohydrate disequilibrium resulting in damage to the central nervous system. Hypoglycemia is a relatively common metabolic problem seen during newborn care. However its definition, management and long term sequalae remain controversial. Hyporglycemia occurs frequently as a transient disorder with excellent prognosis. It also may persist and recur and cause permanent neurological complications. Although the key to effective treatment of hypoglycemia is diagnostic specific, the maintenance of euglycemia is critical to the preservation of central nervous system function. This article discusses physiology of perinatal glucose homeostasis, focusing on evaluation and treatment of hypoglycemia.

On the basis of the inhibitory actions of the somatostatin analogue SMS 201-995 on growth hormone (GH) and glucagon (IRG) secretion we investigated its effects on carbohydrate metabolism of insulin-dependent diabetics. Six patients with no residual insulin secretion were connected to the artificial endocrine pancreas (AEP) and after the establishment of a steady state overnight they were injected either normal saline or 50 micrograms of SMS 201-995 s.c., t.i.d., or 100 micrograms of the same compound b.i.d. Insulin requirements were assessed by the AEP and compared during the 24 h and after the main meals. The inhibition of GH and IRG secretion was evaluated as well. 50 micrograms of SMS analogue t.i.d. induced a significant reduction of insulin requirement (mean +/- SEM) while no significant difference was observed between control and 100 micrograms s.c., b.i.d., nor between 50 micrograms and 100 micrograms. The curve of glucose fluctuations was smoother after 50 micrograms than after 100 micrograms and control. Postprandial IRG secretion was inhibited by both regimens of SMS after lunch and dinner. GH secretion was significantly inhibited after all meals during the days of analogue administration. SMS 201-995 analogue appears to have a remarkable antidiabetic activity as shown by the sparing of administered amount of insulin, suppression of counter-insulin hormones and smoothing of blood glucose curve. It may constitute a safe and effective adjunctive measure in the management of insulin-dependent diabetics.

There exists an apparent relationship between thyroid hormones and other substrates known to influence carbohydrate homeostasis. Thyroid hormones, for example, increase lipolysis in rat adipocytes in response to glucagon, and reciprocally, T3 administration increases glucagon receptors and thus stimulates glycerol production. In order to further study these relationships we determined whether dexamethasone, streptozotocin-induced diabetes, glucose feeding and carbohydrate content of diet altered murine hepatic nuclear T3 receptors. Rats were divided into one of several protocols:(1) dexamethasone was administered i.p. at a dose of approximately 1.5 mg/kg for 6–10 days, (2) streptozotocin was administered in a dose of approximately 65 mg/kg and the rats were sacrificed and the nuclei studied approximately 7–10 days later. Mean (± SE) plasma glucose at the time of sacrifice was 539 ± 33 mg/dl (n=5) in the streptozotocin treated rats and 159 ± 8 mg/dl (n=5) in the saline injected control animals; (3) in the glucose studies, rats were divided into either a fasted group, a fasted group that was given 50% dextrose in their drinking water or into a group allowed to eat normally. These groups were given the appropriate diet for 3 days at which time they were sacrificed; (4) to assess the effect of carbohydrate content of the diet, rats were pair fed and allowed to eat either a diet containing 79% carbohydrate, 9% protein and 5% fat or a diet containing 52% carbohydrate, 36% protein and 5% fat. The diets contained adequate amounts of all other necessary nutrients. Rats were sacrificed after ingesting either of these diets for approximately 14 days. In all studies, hepatic nuclei were isolated and studied as previously reported (Endocrinology 107:1081, 1980). In dexamethasone treated rats, the maximal percentage binding of 125 I-T3 per mg DNA was 18.8 ± 2.8 (n=4) in normal non-injected rats, 21.2 ± 5.7 (n=7) in saline injected rats and 16.8 ±3.9 (n=7) in dexamethasone injected rats. The difference between the saline injected and dexamethasone injected rats was statistically significant (p

Altered carbohydrate metabolism has been reported during episodes of neo natal infection. To document that there is more rapid glucose disappearance during infection, intravenous glucose tolerance tests (IVGTT) and serial plasma growth hormone and insulin levels were determined in eight full-term neonates during the first three days of an acute episode of infection and during convalescence, 5 to 15 days later. Eight healthy infants were each studied once using the same study protocol. Glucose disappearance rates, measured as Kt of glucose, were increased (p < 0.01) during both the acute septic period (3.7 ± 0.3% disappearance/min; mean ± S.E.M.) and convalescent period (2.5 ± 0.2%/min) when compared with values in control infants (1.3 ± 0.3%/min). Gram-negative, gram-positive, and viral infections were all associated with rapid glucose disposal. The ab normality in carbohydrate homeostasis persisted for at least 5 to 15 days after treatment was begun. Baseline and stimulated (20-minutes post bolus glucose infusion) plasma insulin and growth hormone levels did not differ among the groups. Thus, there is no evidence that hyperinsulinism produced the rapid glucose disappearance rate and enhanced glucose utilization. The reason for the disturbed carbohydrate metabolism in neonatal infections remains un known.

In an attempt to differentiate the effect of fenfluramine hydrochloride from that of caloric restriction on carbohydrate tolerance in patients with lipodystrophy, parameters of carbohydrate homeostasis were studied in patients with lipodystrophy during periods offenfluramine treatment and during periods of caloric restriction. Although carbohydrate tolerance appeared to improve initially in one patient when treated with fenfluramine, this improvement did not persist. No beneficial influence of fenfluramine on carbohydrate tolerance could be identified in the other patients studied. By contrast, all patients demonstrated an improvement in carbohydrate tolerance in response to caloric restriction. These data suggest that caloric restriction improves carbohydrate tolerance in patients with lipodystrophy whereas fenfluramine, in the absence of caloric restriction, has no long-term beneficial effect.

Increased understanding of maternal-fetal carbohydrate homeostasis together with modern perinatal technology now provides a more rational basis for obstetric management of the pregnant diabetic patient. These concepts were applied at MacDonald House in the care of 96 diabetic pregnant women over a two-year period. Pregnancy outcomes were compared with prior experiences with the same group of women. The perinatal mortality rate was reduced from 13.5 to 4.2%, and the rate of macrosomia (infants large for gestational age) was reduced from 30.9 to 17.7%. Patients with gestational diabetes, with a prior loss rate of 8.3%, suffered no losses in the current series. Maternal age was not found to correlate with an untoward outcome in this subgroup.

The effects of manganese (Mn) deficiency on carbohydrate metabolism in the Sprague-Dawley rat were investigated. Oral glucose tolerance tests were performed on offspring from Mn-sufficient female rats fed 45 micrograms Mn per gram diet (C-C), offspring from Mn-deficient female rats fed 1 microgram Mn per gram diet (D1-D1) and rats not exposed to Mn deficiency in utero but fed D1 diet from weaning to maturity (D1). Mn-deficient rats, D1 and D1-D1, had significantly lower concentrations of Mn in liver, kidney, heart and pancreas than controls. D1-D1 rats responded with a diabetic type of glucose tolerance curve when given oral glucose. Insulin levels of D1-D1 rats were not commensurate with their high glucose levels. Measurements made by using an isolated perfused-pancreas preparation indicate that insulin output due to release of stored hormone was 76% of control levels in D1-D1 rats. This suggests either lower insulin stores or impaired release of insulin in D1-D1 rats. Second phase insulin release was also significantly lower in D1-D1 rats than in controls. Pancreatic insulin content was 63% of control levels in D1-D1 rats, further supporting the idea of lower insulin stores in Mn-deficient rats. No differences in plasma glucose levels were observed between D1 rats and controls after an oral-glucose load. These findings indicate that dietary Mn deficiency can result in impaired insulin secretion producing impaired carbohydrate metabolism; however, the timing of the deficiency may be a critical factor in the expression of this abnormality.

Somatostatin, a peptide inhibitor of growth hormone release originally isolated from the hypothalamus, is also present in D cells of pancreatic islets. Its ability to inhibit the secretion of insulin and glucagon suggests that it may be a local regulator of pancreatic A- and B-cell function. Studies using synthetic somatostatin have provided evidence that glucagon is a physiologically important hormone that exacerbates the consequences of insulin deficiency in human diabetes mellitus. The ability of somatostatin to diminish both fasting and postprandial hyperglycemia and to forestall the development of ketoacidosis after withdrawal of insulin in insulin-dependent diabetics suggests a potential therapeutic use of this agent in diabetes. Presently, however, its short half-life and diverse actions preclude such use and have prompted the search for more specific and longer-acting analogs. ( Arch Intern Med 137:659-666, 1977)

The rat appears to be unable to utilize glucose during hypothermia. The objective of this study was to examine carbohydrate homeostasis during induction, hypothermia, and rewarming phases. Groups of normothermic animals were euthanized to serve as time controls for comparison. Hypothermia (15 degrees C) was produced by exposure to helox (80% helium:20% oxygen) at 0 +/- 1 degree C. Hyperglycemia was noted during the induction process (169 +/- 8 in control vs 326 +/- 49 mg/dl). Serum glucose increased further during 4 hr of hypothermia, but following rewarming (Tre of 33 +/- 1 degrees C) was reduced (153 +/- 16 mg/dl) significantly (P less than 0.05). Serum insulin was depressed during hypothermic induction (from 48 +/- 4 in controls to 19 +/- 3 microU/ml in hypothermic rats) and increased only slightly during the arousal process, remaining significantly lower than in normothermic subjects. Initial hepatic, skeletal muscle, and cardiac glycogen concentrations were reduced 34, 68, and 75%, respectively, during hypothermic induction. While liver glycogen decreased further during 4 hr of hypothermia, skeletal and cardiac stores increased markedly. During rewarming, hepatic glycogen was markedly decreased, while skeletal and cardiac stores were maintained. These data suggest that hyperglycemia in the hypothermic rat can be accounted for by glycogenolysis and hypoinsulinemia. In addition, this study indicates repletion of skeletal and cardiac muscle glycogen during maintained hypothermia and sparing of muscle glycogen during rewarming.

Normalization of plasma glucose concentration with subcutaneous injections of insulin has been difficult. With intravenous insulin delivery, normalization of plasma glucose concentration in adult-onset diabetic patients has been achieved when their plasma insulin concentration was normalized. In juvenile-onset diabetic subjects totally lacking endogenous insulin, the effect of normalization of the plasma insulin concentration has not yet been reported. In the present studies, the plasma insulin profile was normalized in four brittle, insulin-dependent diabetic subjects throughout three meals (breakfast, lunch, and supper). Plasma free insulin concentration was assayed after precipitation of endogenous insulin antibodies with polyethylene glycol. Acute meal-related increases in plasma free insulin concentration were achieved with a programmable intravenous insulin delivery system. When plasma insulin profiles were normalized in insulin-dependent diabetic subjects lacking endogenous insulin secretion, an improvement in meal-related glucose excursions was observed. However, complete normalization of plasma glucose concentration was not achieved, suggesting that factors other than plasma insulin concentration modulate carbohydrate homeostasis in brittle diabetes. These factors may include portal vein hypoinsulinemia during peripheral vein insulin infusion, stress hormone concentrations, and tissue insulin resistance.

1. Experiments were carried out to establish what relationship there is between the concentration of ketone bodies in the blood and the concentrations of glycogen in muscle and liver of thirty-six trained and thirty-six untrained rats exercised at the same absolute load. There were, in addition, non-exercised control animals (of which thirty-six were trained and thirty-six untrained) which were studied on the same day. 2. Training occurred on a level treadmill at 0.2 m/s for 1 h/day, 5 days a week, for 6 weeks. The untrained animals ran on the treadmill every 3rd day for 5 min to maintain familiarity with treadmill running without training them. 3. At the end of the 6th week, the experimental animals ran for 1 h at 0.2 m/s on a level treadmill. Blood 3-hydroxybutyrate and tissue glycogen concentrations were measured at the beginning and immediately after exercise, and then every 30 min for 2 h. 4. Physically trained rats had higher pre- and immediate post-exercise liver glycogen concentrations than untrained rats: 413 +/- 15 and 300 +/- 8 mumol/g before exercise in trained and untrained rats respectively, and 225 +/- 8 and 166 +/- 3 mumol/g immediately after (P less than 0.05). 5. Muscle glycogen, which was also higher in trained than in untrained rats, was resynthesized at approximately the same rate in the two groups of animals (9 and 11 mumol/(g h), but the trained animals were able to achieve this without further depletion of liver glycogen beyond that which had occurred during exercise. In untrained animals liver glycogen concentrations continued to drop for 60 min beyond the end of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous investigators have shown rat submaxillary gland extracts to contain large amounts of material immunologically similar to pancreatic glucagon (SM-IRG). The present studies were designed to assess any physiologic contribution of this material to plasma immunoreactive glucagon (IRG) levels and to overall carbohydrate homeostasis in the rat. Bilateral submaxillary glandectomy or sham surgery was performed on adult male rats. After 2–4 wk, these animals were subjected to arginine or epinephrine infusion, fasting, insulin-induced hypoglycemia, or oral glucose loads. No measurable differences could be found between animals with or without submaxillary glands with respect to basal plasma levels of IRG, immunoreactive insulin (IRI), blood glucose (BG), or to the response of these parameters to any of the conditions tested. Furthermore, when eviscerated animals (without gastrointestinal tract or pancreas, but with intact liver and kidneys) were studied with or without submaxillary glands, no significant differences were found in either basal or stimulated levels of plasma IRG and BG. We conclude that SM-IRG makes no significant contribution to either plasma IRG or the metabolism of carbohydrates in the rat, even when other known sources of IRG have been surgically removed. While being unable to document any apparent role for SM-IRG in the maintenance of carbohydrate homestasis, we did observe dynamic changes in the glandular content of SM-IRG that occurred with the onset of puberty in both male and female weanling rats. The possibility, thus, remains that SM-IRG may be physiologically important, but in areas not necessarily related to carbohydrate metabolism.

Najjar, S., Salem, G. and Idriss, Z. (Department of Pediatrics, The American University of Beirut, Beirut, Lebanon). Congenital generalized lipodystrophy. Acta Paediatr Scand, 64:273, 1975.–Six patients with congenital generalized lipodystrophy are described. They had generalized paucity of fat tissue, acanthosis nigricans, prominent superficial veins and muscle hypertrophy. They were mentally retarded. Three had corneal opacities. They had normal external genitalia and none was tall for age. Their bone age was advanced and some had minor skeletal anomalies and nephromegaly. The muscle histology on light microscopy was normal. The majority had elevated serum aldolase and to a lesser degree serum lactic dehydrogenase and creatinine phosphokinase. Four of five examined had a myopathic electromyogram. They had normal or minimally deranged liver function tests. The fatty liver infiltration in one seems to be progressive. Four had a normal and two an abnormal metyrapone test. They had an age-dependent abnormality of growth hormone, insulin and carbohydrate homeostasis.

Patients with nonketotic diabetes mellitus, who were both obese and had significant fasting hyperglycemia (mean plasma glucose = 310 mg/100 ml), were fasted for 10 days. There was a prompt drop of plasma glucose levels as the result of the caloric deprivation with a mean fall of approximately 200 mg/dl at the end of the fast. The drop in plasma glucose level that occurred during the fast was associated with a drop in plasma insulin level. Fasting plasma glucose concentration rose immediately after food intake was resumed and stabilized within 3--4 days at levels halfway between the initial and the lowest value. At this time, the patients also seemed capable of disposing of an oral glucose load more efficiently. The apparent improvement in carbohydrate homeostasis observed after the fast could not be attributed to an increase in insulin response, but was associated with some amelioration of the insulin resistance that characterizes these patients. Unfortunately, the beneficial effects of the 10-day period of caloric deprivation were transitory and fasting plasma glucose values had returned to prefast levels in most patients within a few months.

The effects of hibernation on pancreatic insulin, glucagon, somatostatin, and pancreatic polypeptide was investigated in the golden mantled ground squirrel (Citellus lateralis). During hibernation, pancreatic organ weight decreased to 57% of the nonhibernating weight. The content of all four pancreatic hormones during hibernation was significantly reduced. The concentrations of insulin, pancreatic polypeptide and somatostatin, but not of glucagon, were significantly reduced during hibernation. The maintenance of the pancreatic glucagon concentration during hibernation may be related to its role in counter-regulation and carbohydrate homeostasis during fasting.

In the decade since the discovery of specific opioid receptors in the brain, there have been rapid advances in our understanding of the physiological and pathological roles of the endogenous opioid systems in humans. Endogenous opioid peptides have been demonstrated to play a role as modulators of a number of hormonal functions in humans. In particular they appear to inhibit luteinizing hormone and ACTH release, and the response of arginine vasopressin to osmotic stimuli. They appear to participate in the modulation of carbohydrate homeostasis. In pathophysiological states, they appear to play a role in the decreased pulsatile luteinizing hormone release seen in patients with prolactinomas. Circulating beta-endorphin appears to be an important regulator of immune function. Preliminary studies in humans have suggested a role for endogenous opioid peptides in appetite regulation. In the last few years, a few case reports have suggested the possibility of a series of syndromes due to endogenous opioid excess. Within the next decade, we can expect to see the routine use of opioid antagonists in a variety of pathophysiological states.

Carbohydrate homeostasis was evaluated in 47 girls with Turner syndrome and in 25 "short normal" girls by means of an oral glucose tolerance test. Of the Turner patients 34% showed an impaired glucose tolerance vs 8% of the controls (chi 2 = 5.9, P less than 0.05). Mean glucose levels were significantly higher and mean insulin levels and insulinogenic index significantly lower in young Turner patients aged 5-12 years but not in adolescents aged 12-16 years. In both groups of patients, insulin levels and the insulinogenic index were significantly lower than those of the controls. In Turner patients between 12 and 16 years, carbohydrate tolerance improved and this may be explained by the lack of oestrogen release in these patients. Glucose tolerance was normal in patients with mosaicism. We conclude that (1) carbohydrate tolerance is defective in young children with Turner syndrome but improves in puberty due to the almost complete absence of oestrogen-progestogen secretion; (2) a difference in carbohydrate tolerance is evident depending on karyotype.

The effects of manganese (Mn) toxicity on carbohydrate homeostasis was examined in Sprague-Dawley and Osborne-Mendel rats. Mn injection was followed by increases in Mn concentration in both liver and pancreas. Concentrations of Mn in the pancreas increased more rapidly than in the liver. Plasma insulin levels decreased, plasma glucose levels increased, and a spike in glucagon concentration was observed following Mn injection. Increases in blood glucose in response to Mn injection were also observed in 24- and 48-h fasted rats, although the magnitude of the increase was less than that observed in fed rats. Both strains of rats appeared to respond similarly to Mn injection. The present studies demonstrate that acute Mn injection can affect glucose homeostasis. These effects may be mediated through altered endocrine pancreatic function.

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were 30–80 mg 100 ml lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.

Thus, this brief account of our experiments has indicated that homeostasis may be maintained by “behavioral” as well as “physiological” mechanisms. How these two mechanisms probably operate and inter-react in intact organisms has been discussed elsewhere6, 7. It is hoped that this concept of “behavioral” mechanisms may be of use in the field of carbohydrate metabolism on the one hand to the experimenters who are working on animals, and on the other to the clinical workers on man. It should make the experimenters aware that animals themselves with their dietary selections and other forms of behavior may attempt to regulate carbohydrate metabolism; and the clinicians that patients may do likewise. It must be added that in man the operation of “behavioral” mechanisms may be complicated or confused by beliefs, habits, or social pressure.

SummaryRegulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.

Experimental hypothermia and natural hibernation are two forms of hypometabolism with recognized physiological changes, including depression of endocrine and metabolic functions. To better understand functional changes, helox (i.e., helium and oxygen (80:20) mixtures) and low ambient temperatures have been used to induce hypothermia in hamsters and rats. Both clinical and biological survival, i.e., survival without recovery and survival with recovery from hypothermia, respectively, are related to depth and length of hypothermia. In the rat, body temperatures of 15 degrees C for periods greater than 6-10 h greatly restrict biological survival. The role of glucocorticoids in enhancing thermogenic capacity of rats was assessed using triamcinolone [correction of triamcinalone] acetonide. In the hamster, treatment with cortisone acetate prolonged both clinical and biological survival. Hypothermic hamsters continue utilizing circulating glucose until they become hypoglycemic and die. Hypothermic rats do not utilize glucose and respond with a significant hypoinsulinema. The role of endocrines in the regulation of carbohydrate homeostasis and metabolism differs in hibernation and hypothermia. Glucocorticoids influence the hypothermic response in both species, specifically by prolonging induction of hypothermia in rats and by prolonging survival in hypothermic hamsters.

A partially purified amylase inhibitor given with a single meal causes maldigestion of carbohydrate, increases delivery of carbohydrate to the ileum, and reduces postprandial plasma glucose. To determine the effect of more prolonged administration of the inhibitor on gastrointestinal function and carbohydrate tolerance, we studied 6 non-insulin-dependent diabetics (3 previously treated with oral agents and 3 treated with diet alone) for 3 wk while they ate a weight-maintenance diet. Patients taking oral agents continued them during the first week. During the second week, 4-6 g of the inhibitor was given with each meal. Capillary blood glucose concentration was measured before each meal and 90 min postprandially. On the last day of each week venous blood samples for glucose, hormones, and lactic acid analysis and a quantitative stool culture were obtained. Total carbohydrate absorption was estimated by comparing postprandial breath hydrogen on study days 7, 14, and 21 with breath hydrogen after ingesting 15 g of lactulose on days 0, 15, and 22. There 24-h stools were collected and weighed at the end of each week and analyzed for carbohydrate, lactic acid, short-chain fatty acids, pH, dry matter, amylase, and fat. The inhibitor significantly (p less than 0.05) reduced postprandial plasma glucose, C-peptide, insulin, and gastric inhibitory polypeptide concentrations, significantly increased (p less than 0.05) breath hydrogen excretion, and caused carbohydrate malabsorption. Diarrhea occurred the first day the inhibitor was ingested, but thereafter cessation of diarrhea was associated with changes in the metabolism of carbohydrate by colonic flora. As the amylase inhibitor improves carbohydrate homeostasis and is not associated with continuing diarrhea, it may be a useful adjuvant in the treatment of patients with non-insulin-dependent diabetes mellitus.

Alterations in insulin and glucagon levels might account for the plasma amino acid imbalance of cirrhotics. In order to verify this hypothesis we evaluated basal insulin, glucagon, branched-chain amino acids, aromatic amino acids, and free tryptophan in 13 controls and 37 cirrhotics divided on the basis of their mental state; in 4 patients the hormonal and amino acid patterns were sequentially studied during various stages of encephalopathy. Glucagon is high in cirrhotics and progressively increases with the worsening of the mental state. Free tryptophan and aromatic amino acids show a similar behavior and significantly correlate with glucagon levels (r = 0.67 and r = 0.81, respectively). On the other hand insulin levels, which are high in cirrhotics without encephalopathy, fall in the presence of deep coma. Insulin did not correlate with any of the plasma amino acids considered. Our data suggest that the catabolic state associated with increased glucagon levels may account for some of the alterations in the plasma amino acid profiles of cirrhotics. Portal-systemic shunting does not seem to be the common cause of both hyperglucagonemia and hyperaminoacidemia. Decreased branched-chain amino acid levels may be related to factors different from those involved in the alterations of carbohydrate homeostasis.

Haemolytic anaemia associated with prominent red cell fragmentation is described in seven patients with long-standing diabetes mellitus. A common freature in the patients was severe microangiopathy as detected by retinal examination and microscopic examination of the kidneys. Renal or pancreatic islet malfunction per se is not involved in the haemolytic syndrome, since red cell abnormalities persisted in one patient for over a year following successful renal and pancreatic transplantation--this, despite the maintenance of normal renal and carbohydrate homeostasis. The kinetics of fragmentation was sutdied by tranfusing snormal type O cells into this type A patient. With reisolation of these cells by the Ashby-technique, rapid and porgressive red cell fragmentation was demonstrated by: (a) membrane lipid loss; (b) osmotic fragility increase; and (c) increase in mean cell haemoblobin concentration. This studies indicate that a red-cell-fragmentation haemolytic anaemia may occur in long-standing diabetes mellitus, related to the angiopathy of this disease and not to insulin deficiency or renal malfunction.

Publisher Summary This chapter discusses the effect of an intact animal on carbohydrate homeostasis when insulin is injected into central nervous system (CNS) structures or into the carotid artery. The mode of action of insulin on the cells of the putative insulin-sensitive CNS center remains unclear. It appears that it may work through a non-glucose action of the hormone, as pretreatment of the animals with 2-deoxy-D-glucose did not eliminate the hypoglycemic effect of insulin injected into the carotid artery. Deep anesthesia did have an inhibitory effect on the fall of glucose after intracarotid insulin injection as it does on many other autonomie neural functions. The liver, having a pivotal role in glucose metabolism both by storing excess carbohydrate in form of glycogen and by releasing it into the circulation when required, was the natural candidate to be the target (effector) organ of CNS-mediated glucoregulatory impulses. This was substantiated when functional hepatectomy, that is, ligation of both portal and hepatic circulation resulted in elimination of the glucose differential between animals that received intracarotid insulin and their buffer-injected controls. A considerable quantity of native insulin was shown to be present in the CNS. This was demonstrated by acid ethanol extraction and concentration followed by radioimmunoassay.

Twenty-one patients were seen with the diagnosis of chronic lymphocytic thyroiditis in the Endocrine Clinic during 1965–1972. Three patients developed clinical diabetes mellitus at intervals from one month to three years after the diagnosis of thyroiditis was confirmed. An additional patient, a member of the study group reported here, had asymptomatic glucose intolerance initially and developed insulin-dependent diabetes mellitus six months after the diagnosis of thyroiditis was established. Standard glucose tolerance tests were performed on 12 additional patients. One of these patients had unequivocal evidence of chemical diabetes; one other had a borderline abnormal oral glucose tolerance test. The remaining ten patients had normal glucose and insulin values during the OGTT. These studies indicate that children with chronic lymphocytic thyroiditis are at increased risk of developing diabetes mellitus when compared with the normal childhood population.

The activities of two liver gluconeogenic enzymes, pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK), as well as liver glycogen and plasma glucose, insulin, and glucagon were measured in first- and second-generation, manganese-sufficient (control) and manganese-deficient (Mn-) adult rats. Pyruvate carboxylase activity of first generation male Mn- rats was higher than that of controls in both the fed and fasted states. In contrast, PC activity in second generation male Mn- rats was lower than control levels. In female rats, PC activity was lower than controls in both fed, first- and second-generation Mn- rats; in the fasted state, PC activity was either the same or higher than controls. Phosphoenolpyruvate carboxykinase activity was lower in male first generation Mn- rats than in controls, but there was no difference in PEPCK activity in second-generation animals. Phosphoenolpyruvate carboxylase activity was lower in both fed and fasted Mn- female rats than in controls. Plasma insulin levels were lower in the deficient rats than in controls, whereas plasma glucagon levels were similar. Manganese-deficient rats had higher concentrations of liver glycogen than their controls. These findings provide further evidence that manganese affects carbohydrate homeostasis; however, the response of the animal to manganese deficiency depends on the parameter studied and the timing of the deficiency.

Published information derived from studies of prostaglandins on carbohydrate homeostasis and insulin secretion has been considered somewhat controversial by many investigators. An analysis of the literature published since 1876 suggests that this controversy has its roots in imprecise terminology and overgeneralization of data rather than irreconcilable scientific experiments. The two major sources of confusion have been failure to distinguish glucose-induced acute insulin responses from insulin secretion in general and failure to appreciate that the behavior of indomethacin is not consistent with the effects of other nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors) on glucose homeostasis and insulin secretion. When acute insulin responses to glucose specifically are examined and data from indomethacin studies are excluded, the available information consistently indicates that prostaglandin E has adverse effects on glucose homeostasis and insulin secretion.

In previous studies [1, 2] we have shown that acarbose, an α-glucosidase inhibitor which slows carbohydrate absorption, can decrease insulin requirements of diabetics, as assessed in acute experiments with the artificial endocrine pancreas. Moreover, it creates a smoothening of blood glucose fluctuations over 24 h. The aim of this study was to investigate whether the addition of acarbose, 200–400 mg per day, leads to an improvement of carbohydrate homeostasis in type II diabetics on diet or oral agents. Ninety patients (24 on diet, 21 on phenformin, 18 on glibenclamide, 16 on a combination of glibenclamide and phenformin, and 12 with secondary failure of oral antidiabetic therapy) were studied. The regimen of oral agents remained the same during the whole period of observation.

Sequential glucose flux studies were carried out in five normal and six epileptic children and ten adult volunteers using [6,6-2H2]glucose to determine the effect of ketosis on carbohydrate homeostasis in children and adults. All subjects were studied after 14 and 30-38 h of fasting while consuming a normal diet and the epileptic children under 14 h of fasting while consuming an isocaloric ketogenic diet (75% fat wt/wt). Glucose flux, when expressed per kilogram body weight, was inversely correlated with the degree of ketosis in children (P less than 0.001) and in adults (P less than 0.01), but not when both children and adults were considered together (r = 0.078). When glucose flux was corrected for estimated brain weight, the relationship between glucose flux and ketonemia was linearly related in children (P less than 0.001), in adults (P less than 0.02), and when all subjects were considered together (P less than 0.001). The inverse relationship between ketonemia and glucose flux corrected for estimated brain mass is consistent with a partial replacement of glucose by ketone bodies for cerebral metabolism and may provide a more rational means of expressing glucose flux data to take into account the higher brain-to-body ratio in children.