Resveratrol enhances brown adipocyte formation and function by activating AMP-activated protein kinase (AMPK) α1 in mice fed high-fat diet.

SCOPE: Enhancing the formation and function of brown adipose tissue (BAT) increases thermogenesis and hence reduces obesity. Thus, we investigate the effects of resveratrol (Resv) on brown adipocyte formation and function in mouse interscapular BAT (iBAT). METHODS AND RESULTS: CD1 mice and stromal vascular cells (SVCs) isolated from iBAT were treated with Resv. Expression of brown adipogenic and thermogenic markers, and involvement of AMP-activated protein kinase (AMPK)α1 were assessed. In vivo, Resv-enhanced expression of brown adipogenic markers, PR domain-containing 16 (PRDM16) and thermogenic genes, uncoupling protein 1 (UCP1) and cytochrome C in iBAT, along with smaller lipid droplets, elevated AMPKα activity and increased oxygen consumption. Meanwhile, Resv promoted expression of PRDM16, UCP1, PGC1α, cytochrome C and pyruvate dehydrogenase (PDH) in differentiated iBAT SVCs, suggesting that Resv enhanced brown adipocyte formation and function in vitro. In addition, Resv stimulated AMPKα and oxygen consumption in differentiated iBAT SVCs. However, the promotional effects of Resv were diminished by AMPK inhibition or AMPKα1 knockout, implying the involvement of AMPKα1 in this process. CONCLUSION: Resv enhanced brown adipocyte formation and thermogenic function in mouse iBAT by promoting the expression of brown adipogenic markers via activating AMPKα1, which contributed to the anti-obesity effects of Resv.

Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) α1.

OBJECTIVE: Development of brown-like/beige adipocytes in white adipose tissue (WAT) helps to reduce obesity. Thus we investigated the effects of resveratrol, a dietary polyphenol capable of preventing obesity and related complications in humans and animal models, on brown-like adipocyte formation in inguinal WAT (iWAT). METHODS: CD1 female mice (5-month old) were fed a high-fat diet with/without 0.1% resveratrol. In addition, primary stromal vascular cells separated from iWAT were subjected to resveratrol treatment. Markers of brown-like (beige) adipogenesis were measured and the involvement of AMP-activated protein kinase (AMPK) α1 was assessed using conditional knockout. RESULTS: Resveratrol significantly increased mRNA and/or protein expression of brown adipocyte markers, including uncoupling protein 1 (UCP1), PR domain-containing 16, cell death-inducing DFFA-like effector A, elongation of very long-chain fatty acids protein 3, peroxisome proliferator-activated receptor-γ coactivator 1α, cytochrome c and pyruvate dehydrogenase, in differentiated iWAT stromal vascular cells (SVCs), suggesting that resveratrol induced brown-like adipocyte formation in vitro. Concomitantly, resveratrol markedly enhanced AMPKα1 phosphorylation and differentiated SVC oxygen consumption. Such changes were absent in cells lacking AMPKα1, showing that AMPKα1 is a critical mediator of resveratrol action. Resveratrol also induced beige adipogenesis in vivo along with the appearance of multiocular adipocytes, increased UCP1 expression and enhanced fatty acid oxidation. CONCLUSIONS: Resveratrol induces brown-like adipocyte formation in iWAT via AMPKα1 activation and suggest that its beneficial antiobesity effects may be partly due to the browning of WAT and, as a consequence, increased oxygen consumption.

Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men.

Growth hormone (GH), insulin-like growth factor I (IGF-I), and testosterone (T) are important mediators of muscle protein synthesis, and thus muscle mass, all of which decline with age. We hypothesized that circulating hormones would be related to the transcriptional levels of their respective receptors and that this expression would be negatively related to expression of the myostatin gene. We therefore determined content of mRNA transcripts (by RT-PCR) for GH receptor (GHR), IGF-I, androgen receptor (AR), and myostatin in skeletal muscle biopsy samples from 27 healthy men >65 yr of age. There were no significant relationships between age, lean body mass, or percent body fat and transcript levels of GHR, IGF-I, AR, or myostatin. Moreover, there were no significant correlations of serum GH, IGF-I, or T with their corresponding target mRNA levels (GHR, intramuscular IGF-I, or AR) in skeletal muscle. However, GHR was negatively correlated (r = -0.60, P = 0.001) with myostatin mRNA levels. The lack of apparent relationships of muscle transcripts with their respective ligands in healthy older adults suggests that age-related deficits in both GH and T may lead to an increase in myostatin expression and a disassociation in autocrine IGF-I effects on muscle protein synthesis, both of which could contribute to age-related sarcopenia.

Sequence conservation among fish myostatin orthologues and the characterization of two additional cDNA clones from Morone saxatilis and Morone americana.

Myostatin (MSTN) negatively regulates mammalian skeletal muscle growth and development by inhibiting myoblast proliferation. Mice and cattle possessing mutant MSTN alleles display a 'double muscling' phenotype characterized by extreme skeletal muscle hypertrophy and/or hyperplasia. MSTN orthologues have been previously characterized in 12 vertebrate species, including the white bass Morone chrysops. Presented herein is the identification and characterization of novel cDNA clones from two additional Morone species: saxatilis (striped bass) and americana (white perch), which were obtained by PCR amplification and subsequent TA-cloning. The predicted amino acid sequence of each cDNA clone contains a putative signal sequence, conserved cysteine residues and a RXXR proteolytic processing site. The different Morone proteins were 97-99% identical to each other and approximately 91, 81, 68 and 67% identical to the tilapia, zebrafish, mammalian and avian proteins, respectively. However, the bioactive domains, which lie downstream of each processing site, were considerably more conserved. They were 99-100% identical within the genus and were approximately 99, 95, 88 and 88% identical to the tilapia, zebrafish, mammalian and avian domains, respectively. This high level of sequence conservation among all known MSTN orthologues suggests that the structure/function relationship of each is equally well conserved among vertebrates.

Isolation and characterization of myostatin complementary deoxyribonucleic acid clones from two commercially important fish: Oreochromis mossambicus and Morone chrysops.

In mammals, skeletal muscle mass is negatively regulated by a muscle-derived growth/differentiating factor named myostatin (MSTN) that belongs to the transforming growth factor-beta superfamily. Although putative MSTN homologs have been identified from several vertebrates, nonmammalian orthologs remained poorly defined. Thus, we isolated and characterized MSTN complementary DNA clones from the skeletal muscle of the tilapia Oreochromis mossambicus and the white bass Morone chrysops. The nucleic and amino acid sequences from both fish species are highly homologous to the previously identified mammalian and avian orthologs, and both possess conserved cysteine residues and putative RXXR proteolytic processing sites that are common to all transforming growth factor-beta family members. Western blotting of conditioned medium from human embryonal kidney (HEK293) cells overexpressing a His-tagged tilapia MSTN indicates that the secreted fish protein is processed in a manner similar to mouse MSTN. However, in contrast to mice, MSTN expression in tilapia is not limited to skeletal muscle as it occurs in many tissues. Furthermore, the timing of MSTN expression in developing tilapia larvae coincides with myogenesis. These results suggest that the biological actions of MSTN in the tilapia and possibly in other fishes may not be limited to myocyte growth repression, but may additionally influence different cell types and organ systems.

Endocrine regulation of G-protein subunit production in an animal model of type 2 diabetes mellitus.

Adipocyte beta-adrenergic sensitivity is compromised in animal models of obesity and type 2 diabetes. Although changes in the membrane concentrations of G-protein alpha subunits (Galpha) have been implicated, it remains to be determined how these changes are affected by insulin resistance in the different animal models. Because previous studies used young animals, we measured the concentrations of Galpha and Gbeta subunits in epididymal fat from aged (48 weeks old) db/db mice and from their lean littermates to more closely reproduce the model of type 2 diabetes mellitus. Levels of immunoreactive Galphas, Galphai(1/2), Galphao and Galphaq/11 were all significantly greater in adipocyte membranes from the db/db mice than in membranes from their lean non-diabetic littermate controls. Levels of Galphai(1) and Galphai(2) were also individually determined and although they appeared to be slightly higher in db/db membranes, these differences were not significant. Although the levels of both Galphas isoforms were elevated, levels of the 42 and 46 kDa proteins rose by approximately 42% and 20% respectively, indicating differential protein processing of Galphas. By contrast, levels of Galphai3 were similar in the two groups. The levels of common Gbeta and Gbeta2 were also elevated in db/db mice, whereas Gbeta1 and Gbeta4 levels were not different. To determine whether these changes were due to insulin resistance per se or to elevated glucocorticoid production, G-protein subunit levels were quantified in whole cell lysates from 3T3-L1 adipocytes that were stimulated with different concentrations of either insulin or corticosterone. Although none of the subunit levels was affected by insulin, the levels of both Galphas isoforms were increased equally by corticosterone in a concentration-dependent manner. Since glucocorticoids are known regulators of Galphas gene expression in many cell types and in adipocytes from diabetic rodents, the results presented herein appear to more accurately reflect diabetic pathophysiology than do those of previous studies which report a decrease in Galphas levels. Taken together, these results indicate that most of the selective changes in G-protein subunit production in adipocytes from this animal model of type 2 diabetes may not be due to diminished insulin sensitivity, but may be due to other endocrine or metabolic abnormalities associated with the diabetic phenotype.

Insulin regulation of a novel WD-40 repeat protein in adipocytes.

A 400 bp PCR product generated with degenerate primers derived from the glucagon-like peptide-1 receptor was used to screen a rat skeletal muscle cDNA library. The predicted amino acid sequence of the 978 bp open reading frame has a predicted M(r) of 35 804, an estimated isoelectric point (pI) of 5.31 and contains seven WD-40 repeats, which are common to G-protein beta subunits (Gbeta). Although chemically and structurally similar to Gbeta subunits, the predicted amino acid sequence, when compared with the previously cloned Gbeta isoforms, was found to be only 31-41% similar and thus was named Gbeta-like (GbetaL, 'Gable'). Western blotting of whole-cell lysates and immunoprecipitates of membrane and cytosolic fractions of HEK 293 cells stably overexpressing a carboxy-terminal His-tagged GbetaL indicates that the protein is cytosolic and that it migrates at 42 kDa. A 4 kb transcript was detected in all tissues surveyed by northern blotting; however, an additional 2 kb transcript was detected in testis. Expression of GbetaL mRNA was highest in the brain and testis, followed by lung, heart, kidney, skeletal muscle, spleen and liver. In addition, reverse transcriptase/PCR showed that several other tissues and cell lines express GbetaL. The ubiquitous nature of the tissue expression pattern of GbetaL is similar to that of the insulin receptor, which suggests that insulin may influence GbetaL expression. Indeed, GbetaL protein and mRNA levels, in fully differentiated 3T3-L1 adipocytes, were upregulated by insulin in a concentration-dependent fashion. These changes were highly sensitive to insulin stimulation, being minimally affected by doses as low as 0.1 nM and maximally elevated by 1 nM doses. These data suggest that insulin regulates GbetaL production and imply that some of the actions of insulin may be mediated, in part, by this novel intracellular protein.

Differential expression of a novel seven transmembrane domain protein in epididymal fat from aged and diabetic mice.

To identify novel seven transmembrane domain proteins from 3T3-L1 adipocytes, we used PCR to amplify 3T3-L1 adipocyte complementary DNA (cDNA) with primers homologous to the N- and C-termini of pancreatic glucagon-like peptide-1 (GLP-1) receptor. We screened a cDNA library prepared from fully differentiated 3T3-L1 adipocytes using a 500-bp cDNA PCR product probe. Herein describes the isolation and characterization of a 1.6-kb cDNA clone that encodes a novel 298-amino acid protein that we termed TPRA40 (transmembrane domain protein of 40 kDa regulated in adipocytes). TPRA40 has seven putative transmembrane domains and shows little homology with the known GLP-1 receptor or with other G protein-coupled receptors. The levels of TPRA40 mRNA and protein were higher in 3T3-L1 adipocytes than in 3T3-L1 fibroblasts. TPRA40 is present in a number of mouse and human tissues. Interestingly, TPRA40 mRNA levels were significantly increased by 2- to 3-fold in epididymal fat of 24-month-old mice vs. young controls as well as in db/db and ob/ob mice vs. nondiabetic control littermates. No difference in TPRA40 mRNA levels was observed in brain, heart, skeletal muscle, liver, or kidney. Furthermore, no difference in TPRA40 expression was detected in brown fat of ob/ob mice when compared with age-matched controls. Taken together, these data suggest that TPRA40 represents a novel membrane-associated protein whose expression in white adipose tissue is altered with aging and type 2 diabetes.

Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells stably expressing the human insulin receptor and the rat glucagon-like peptide-1 (GLP-1) receptor (CHO/GLPR) were used to study the functional coupling of the GLP-1 receptor with G proteins and to examine the regulation of the mitogen-activated protein (MAP) kinase signaling pathway by GLP-1. We showed that ligand activation of GLP-1 receptor led to increased incorporation of GTP-azidoanilide into Gs alpha, Gq/11 alpha, and Gi1,2 alpha, but not Gi3 alpha. GLP-1 increased p38 MAP kinase activity 2.5- and 2.0-fold over the basal level in both CHO/GLPR cells and rat insulinoma cells (RIN 1046-38), respectively. Moreover, GLP-1 induced phosphorylation of the immediate upstream kinases of p38, MKK3/MKK6, in CHO/GLPR and RIN 1046-38 cells. Ligand-stimulated GLP-1 receptor produced 1.45- and 2.7-fold increases in tyrosine phosphorylation of 42-kDa extracellular signal-regulated kinase (ERK) in CHO/GLPR and RIN 1046-38 cells, respectively. In CHO/GLPR cells, these effects of GLP-1 on the ERK and p38 MAP kinase pathways were inhibited by pretreatment with cholera toxin (CTX), but not with pertussis toxin. The combination of insulin and GLP-1 resulted in an additive response (1.6-fold over insulin alone) that was attenuated by CTX. In contrast, the ability of insulin alone to activate these pathways was insensitive to either toxin. Our study indicates a direct coupling between the GLP-1 receptor and several G proteins, and that CTX-sensitive proteins are required for GLP-1-mediated activation of MAP kinases.

High potency antagonists of the pancreatic glucagon-like peptide-1 receptor.

GLP-1-(7-36)-amide and exendin-4-(1-39) are glucagon-like peptide-1 (GLP-1) receptor agonists, whereas exendin-(9-39) is the only known antagonist. To analyze the transition from agonist to antagonist and to identify the amino acid residues involved in ligand activation of the GLP-1 receptor, we used exendin analogs with successive N-terminal truncations. Chinese hamster ovary cells stably transfected with the rat GLP-1 receptor were assayed for changes in intracellular cAMP caused by the test peptides in the absence or presence of half-maximal stimulatory doses of GLP-1. N-terminal truncation of a single amino acid reduced the agonist activity of the exendin peptide, whereas N-terminal truncation of 3-7 amino acids produced antagonists that were 4-10-fold more potent than exendin-(9-39). N-terminal truncation of GLP-1 by 2 amino acids resulted in weak agonist activity, but an 8-amino acid N-terminal truncation inactivated the peptide. Binding studies performed using 125I-labeled GLP-1 confirmed that all bioactive peptides specifically displaced tracer with high potency. In a set of exendin/GLP-1 chimeric peptides, substitution of GLP-1 sequences into exendin-(3-39) produced loss of antagonist activity with conversion to a weak agonist. The results show that receptor binding and activation occur in separate domains of exendin, but they are more closely coupled in GLP-1.

Efficacy of preconception care of diabetic women in a community setting.

OBJECTIVE: To determine the impact of informal preconception care of diabetic women on first-trimester glycemia control in a community setting. STUDY DESIGN: Forty-five women with pregestational diabetes underwent a standardized interview regarding their preconception care prior to the index pregnancy. Patients under 14 weeks' gestation had their glycosylated hemoglobin measured; it was used as an index of first-trimester glycemic control. Variables related to glycemic control were analyzed with reference to glycosylated hemoglobin results. RESULTS: Despite a high incidence of counseling and frequent preconception visits, the mean first-trimester glycosylated hemoglobin (+/- SD) was high (10.7 +/- 2.0), and the majority of pregnancies were unplanned. CONCLUSION: Informal and noncentralized preconception care was not effective in preventing first-trimester hyperglycemia in this group of diabetic women. A high rate of unplanned pregnancy and lack of structured preconception care were prevalent and possibly etiologic.

Regulation of insulin-like growth factor-binding proteins in rats with insulin-dependent diabetes mellitus.

As previously reported, activation of the adrenocorticotropic hormone (ACTH)-adrenal cortical axis in rats with insulin-dependent diabetes mellitus (IDDM) reduces their growth and circulating insulin-like growth factor-I (IGF-I) levels and induces a resistance to growth hormone (GH) and IGF-I. The studies reported herein were conducted to determine whether the pituitary and/or adrenal gland influence the changes in basal and GH-stimulated serum concentrations of IGF-binding proteins (IGFBPs) in rats with IDDM. Male rats were made diabetic by injections of streptozotocin. Intact nondiabetic (NonDb), diabetic (Db), hypophysectomized diabetic (HxDb), and adrenalectomized diabetic (AxDb) rats were injected twice daily with 50 micrograms porcine (p) GH or with 0.9% saline for 2 weeks following the surgeries. Changes in serum IGFBP concentrations were determined by Western ligand- or immuno-blot analysis. Neither IGFBP-5 nor -6 was detected in any of the treatment groups. Induction of IDDM increased serum concentrations of IGFBP-1 and -2 and reduced those of IGFBP-3 and -4. Although serum IGFBP-1 and -2 concentrations remained elevated in the HxDb rats compared with the NonDb controls, IGFBP-1 levels were reduced compared with those in the Db controls. Serum IGFBP-3 and -4 were reduced to levels below those in Db controls. Although IGFBP-3 and -4 concentrations were elevated to normal in AxDb rats, the IGFBP-2 concentration was increased above those in both NonDb and Db rats and the IGFBP-1 concentration was reduced. Administration of pGH increased serum IGFBP-4 concentrations in all groups and IGFBP-3 concentrations in all groups except the Db. In addition, pGH reduced the concentration of IGFBP-1 in HxDb rats and nearly abolished it in AxDb rats, but had no effect on IGFBP-1 concentration in NonDb or Db rats. Administration of corticosterone (B; 25 micrograms/ml of 0.9% saline drinking water) to AxDb rats restored Db-like profiles of all IGFBPs. The refractoriness of Db rats to pGH is associated with a failure of the hormone to elevate IGFBP-2 and -3 titers and to reduce those of IGFBP-1. Adrenal B production appears to be responsible for this resistance to GH. However, the elevated IGFBP-2 concentration in Db rats does not appear to be due to B or any other pituitary-controlled or -derived factors. Impaired growth was associated with substantially reduced IGFBP-3 concentrations and elevated IGFBP-1, whereas growth restoration was associated with the opposite changes.

Corticosterone regulation of insulin-like growth factor I, IGF-binding proteins, and growth in streptozotocin-induced diabetic rats.

The experiments reported herein were conducted to determine how corticosterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and streptozotocin (STZ)-induced diabetic rats. Males were bilaterally adrenalectomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP concentrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IG-FBP-6 was detected in any of the treatment groups. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabetic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 were not significantly changed. Adrenalectomy had no affect on tibial growth or plasma IGFBP-1 in these animals. Plasma IGF-I, IGFBP-1 and -3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that did not receive corticosterone. Plasma IGFBP-4 was inversely related to the amount of STZ injected in these animals, and IGFBP-2 was elevated in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IGF-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increased in proportion with the dose of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypophysectomy or adrenalectomy of rats with insulin-dependent diabetes mellitus partially restores their responsiveness to growth hormone.

The studies reported herein were conducted to confirm that the pituitary gland is involved in maintaining growth hormone (GH) resistance in rats with insulin-dependent diabetes mellitus (IDDM) and to determine whether the adrenocorticotropic hormone (ACTH)-adrenal cortical axis is responsible. The rats were made diabetic by injecting streptozotocin (85 mg/kg body wt) IP once daily on two consecutive days. They were then injected with 15 IU insulin SC twice daily on two consecutive days to enable them to survive hypophysectomy or adrenalectomy. Intact nondiabetic (NonDb), diabetic (Db), hypophysectomized diabetic (HxDb), and adrenalectomized diabetic (AxDb) rats were injected twice daily with 50 micrograms porcine (p) GH or with 0.9% saline for 2 weeks following the surgeries. Serum glucose levels of the saline-injected Db, HxDb, and AxDb rats were significantly greater than those of the NonDb rats by 106%, 65% and 49%, respectively. However, the levels in the HxDb and AxDb animals were significantly lower than those of the Db group by 20% and 28%, respectively. Injections of pGH into NonDb rats increased serum glucose concentrations by 38%, over their saline-treated controls, and by 29% in AxDb rats. This diabetogenic effect of GH was not seen in any other group. Administration of pGH to Db rats failed to increase body weight gain, tall growth, tibial epiphysial plate width, or serum IGF-I concentration over saline-injected controls. By contrast, HxDb and AxDb rats injected with pGH showed significant increases in all four growth parameters. Total serum IGF-I concentrations in AxDb rats injected with pGH equaled those in NonDb controls. To determine whether the lack of corticosterone (B) in the AxDb rats was responsible for the reduced hyperglycemia and restored responsiveness to pGH, AxDb rats were given B in their drinking water at 5 or 25 micrograms/ml. Administration of B reduced the beneficial effects of adrenalectomy by restoring hyperglycemia and growth impairment, and partially restored resistance to the pGH injections. These studies confirm that the pituitary contributes to diabetic growth impairment and show that the ACTH-adrenal cortical axis is primarily responsible for the GH-resistant state that develops in rats with IDDM.

Effects of fasting, medium glucose, and amino acid concentrations on prolactin and growth hormone release, in vitro, from the pituitary of the tilapia Oreochromis mossambicus.

Previous investigations have shown that the release of PRL and GH from the tilapia pituitary is directly sensitive to osmotic pressure and a variety of endocrine and neuroendocrine factors. The present studies were aimed at determining whether the spontaneous release of PRL and GH, in vitro, is: (1) sensitive to the nutritional status of the fish, and (2) responsive to variations in the D-glucose and total amino acid content of the incubation medium. In the first series of experiments, male fish (50 to 60 g) were divided into two groups. One group was fed twice daily for 2 weeks while the second received no food. A nearly homogeneous mass of PRL-secreting cells was dissected from the rostral pars distalis (RPD) and incubated for 18 to 20 hr in either hyposmotic (300 mOsmolal) or hyperosmotic (355 mOsmolal) medium. Similarly, a mass of GH-secreting cells was dissected from the proximal pars distalis (PPD) and incubated for 18 to 20 hr in isosmotic (320 mOsmolal) medium. Fasting was found to alter the total amount of PRL and GH in the culture well (tissue + medium) at the end of the incubations, decreasing PRL and increasing GH. Fasting was also found to both reduce spontaneous PRL release in vitro and suppress its stimulation by reduced osmotic pressure (P less than 0.01). By contrast, fasting resulted in a substantial increase in spontaneous GH release from the PPD in vitro (P less than 0.01). In the second series of experiments, GH release was found to increase as the D-glucose concentration of the medium decreased (P less than 0.01), while prolactin release was unresponsive.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical variables associated with diabetic ketoacidosis during pregnancy.

A retrospective review was conducted of all women with diabetic pregnancies admitted in diabetic ketoacidosis (DKA) to hospitals affiliated with the State University of New York at Buffalo between 1980 and 1990. The experience was combined with a literature review of similar patients described between 1970 and 1990, for a total of 37 admissions for DKA during pregnancy. Emesis and the use of beta-sympathomimetic drugs were considered etiologic in 57% of cases, while patient noncompliance and physician management errors were considered etiologic in 24% and contributory in 16%. Thirty percent of patients admitted with emesis had a prepregnancy history of diabetic gastroenteropathy, thus identifying that group as at particularly high risk for DKA. In the context of modern management, the causes of DKA in pregnancy are related uniquely to pregnancy, and the disorder is largely preventable during pregnancy.

Erythrocyte filterability in normal and high-risk pregnancy.

Erythrocyte filterability was studied longitudinally in normal pregnancy and in certain categories of high-risk pregnancy. Study subjects included ten normal controls, 12 insulin-dependent diabetics, eight gestational diabetics, and five essential hypertensives. Our results indicate that erythrocyte filterability remains relatively stable over the course of normal gestation. We noted no differences between controls and essential hypertensives or gestational diabetics, although a favorable effect of insulin therapy was suggested in gestational diabetics. Erythrocyte filterability and mean arterial blood pressure were not related. Insulin-dependent diabetics demonstrated a significantly elevated and widely varying erythrocyte filterability, and individual patient trends correlated well with outcome. Fibrinogen levels in diabetics rose precipitously and were significantly higher than normal throughout gestation. Fibrinogen levels paralleled changes in erythrocyte filterability, with the two parameters positively correlated. Mean glucose control had no influence on filterability. We conclude that in the diabetic pregnancy, varying erythrocyte filterability is related to altered fibrinogen metabolism and may contribute to perinatal morbidity.