Biomedical subjects

S Efendic

Publications and source records attributed to S Efendic.

At least 55 records · Page 3Linked to original sources

PubMed2000

A probing dose of phenylacetate does not affect glucose production and gluconeogenesis in humans.

Phenylacetate ingestion has been used to probe Krebs cycle metabolism and to augment waste nitrogen excretion in urea cycle disorders. Phenylalkanoic acids, including phenylacetate, have been proposed as potential therapeutic agents in the treatment of diabetes. They inhibit gluconeogenesis in the liver in vitro and reduce the blood glucose concentration in diabetic rats. The effect of sodium phenylacetate ingestion on blood glucose and the contribution of gluconeogenesis to glucose production have now been studied in 7 type 2 diabetic patients. The study was not designed to test whether the changes in glucose metabolism observed in the rat could be reproduced in humans. After an overnight fast, over a period of 1 hour, 4.8 g phenylacetate was ingested, which is the highest dose used to probe Krebs cycle metabolism. Glucose production was measured by tracer kinetics using [6,6-(2)H2]glucose and gluconeogenesis by the labeling of the hydrogens of blood glucose on (2)H20 ingestion. The concentration of phenylacetate in plasma peaked by 2 hours after its ingestion, and about 40% of the dose was excreted in 5 hours. The plasma glucose concentration and production, and the contribution of gluconeogenesis to glucose production, were unaffected by phenylacetate ingestion at the highest dose used to probe Krebs cycle metabolism.

Aged↗

PubMed2000

Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes.

Cholecystokinin (CCK) is a gut hormone and a neuropeptide that has the capacity to stimulate insulin secretion. As insulin secretion is impaired in type 2 diabetes, we explored whether exogenous administration of this peptide exerts antidiabetogenic action. The C-terminal octapeptide of CCK (CCK-8) was therefore infused i.v. (24 pmol/kg x h) for 90 min in six healthy postmenopausal women and in six postmenopausal women with type 2 diabetes. At 15 min after start of infusion, a meal was served and ingested during 10 min. On a separate day, saline was infused instead of CCK-8. In both healthy subjects and subjects with type 2 diabetes, CCK-8 reduced the increase in circulating glucose after meal ingestion and potentiated the increase in circulating insulin. The ratio between the area under the curves for serum insulin and plasma glucose during the 15- to 75-min period after meal ingestion was increased by CCK-8 by 198 +/- 18% in healthy subjects (P = 0.002) and by 474 +/- 151% (P = 0.038) in subjects with type 2 diabetes. In contrast, the increase in the circulating levels of gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), or glucagon after meal ingestion was not significantly affected by CCK-8. The study therefore shows that CCK-8 exerts an antidiabetogenic action in both healthy subjects and type 2 diabetes through an insulinotropic action that most likely is exerted trough a direct islet effect. As at the same time, CCK-8 was infused without any adverse effects, the study suggests that CCK is a potential treatment for type 2 diabetes.

Aged↗

PubMed2000

Regulation of in vitro maturation of stimulus-secretion coupling in fetal rat islet beta-cells.

We have studied the maturation of a glucose-responsive insulin release from fetal rat islets, and specifically investigated the impact of nutrients, alpha-adrenoceptors, imidazoline receptors, and cyclic adenosine monophosphate (cAMP). Islets were isolated from 21 -d-old fetal rats and maintained for 7 d in tissue culture at 3.3 or 11.1 mM glucose and various supplements. Culture in the presence of the nonglucidic nutrient alpha-ketoisocaproic acid (KIC), markedly enhanced both basal and stimulated insulin release from islets cultured at either low or high glucose. Additionally, KIC significantly elevated the insulin content of islets maintained in low glucose, whereas it slightly lowered it in islets cultured at high glucose. Culture with phentolamine, an antagonist of alpha-adrenergic and imidazoline receptors, markedly amplified both basal and glucose-stimulated insulin secretion when added with islets cultured in either low or high glucose. By contrast, the pure alpha2-adrenoceptor antagonist benextramine had no such effects. Addition to culture media of a membrane-permeant agonist (Sp-cAMP[S]) or antagonist (Rp-cAMP[S]) of cAMP-dependent protein kinases types I and II failed to influence basal or glucose-responsive insulin secretory rates at either glucose concentration during culture as well as islet insulin content. In conclusion, islet beta-cell differentiation and functional maturation of the stimulus-secretion coupling can be accelerated in vitro in fetal rat pancreatic tissue by nutrient stimulation, and by interference with imidazoline receptors, whereas cAMP seems virtually ineffective in this respect. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta-cells.

Adrenergic alpha-Antagonists↗

PubMed2000

Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.

Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate, and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemic-hyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU x kg(-1) x min(-1), and glucose was infused at rates of 2.0 +/- 0.2 and 8.1 +/- 0.7 mg x kg(-1) x min(-1), respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation, as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg x kg(-1) x min(-1) (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the high-dose insulin infusion, malonyl-CoA increased from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 +/- 0.06 mg x kg(-1) x min(-1) (P < 0.001). The increase in malonyl-CoA was associated with 30-50% increases in the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 vs. 126 +/- 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle.

Blood Glucose↗

PubMed2000

Influence of acarbose on post-prandial insulin requirements in patients with Type 1 diabetes.

The primary objective of this double-blind, placebo-controlled, randomised cross-over study was to investigate the influence of acarbose on insulin requirement in patients with Type 1 diabetes (T1DM) following a standardised meal. In addition, the study assessed the effects of acarbose on post-prandial triglyceride, glucagon and gastrointestinal peptide levels, gastric emptying, and oxidative glucose metabolism. Following normalisation of their blood glucose, 10 patients received a standardised meal together with acarbose (100 mg) or placebo. Each patient was evaluated twice (separated by 10+/-3 days), and the cross-over study design ensured that they received both acarbose and placebo. The insulin requirement for maintenance of normoglycaemia was assessed using a closed-loop insulin infusion system (artificial pancreas, Biostator). Acarbose produced a statistically significant reduction in mean insulin requirement over a 3-hr period following the meal compared with placebo (5171.7+/-2282.6 mU vs 8074.5+/-3045.4 mU; p=0.003). The level of blood glucose control over the same period was similar in the two groups. Gastric inhibitory polypeptide levels also showed a statistically significant decrease with acarbose treatment compared with placebo for AUC (area under the curve; p=0.006) and Cmax (maximum plasma concentration; p=0.022), but not tmax (time to reach Cmax from the start of the standardised meal; p>0.05). Analysis of the other efficacy parameters revealed no statistically significant differences between acarbose treatment and placebo (p>0.05). These results indicate that acarbose decreases insulin requirement in patients with T1DM without affecting gastric emptying.

Acarbose↗

PubMed1999

Effects of vasopressin-mastoparan chimeric peptides on insulin release and G-protein activity.

Two chimeric peptides, consisting of the linear vasopressin receptor V1 antagonist PhAc-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr, in the N-terminus and mastoparan in the C-terminus connected directly (M375) or via 6-aminohexanoic acid (M391), have been synthesised. At 10 microM concentration, these novel peptides increased insulin secretion from isolated rat pancreatic islet cells 18-26-fold at 3.3 mM glucose and 3.5-5-fold at 16.7 mM glucose. PTX pretreatment of the islets decreased the peptide-induced insulin release. M375 and M391 bind to V1a vasopressin receptors with affinities lower than the unmodified vasopressin antagonist, but with K(D) values of 3.76 nM and 9.02 nM, respectively, both chimeras are high affinity ligands. The GTPase activity and GTPgammaS binding in the presence of these peptides has been characterised in Rin m5F cells. Comparison of the influence of the peptides M375 and M391 on GTPase activity in native and pertussis toxin-treated cells suggests a selective activation of G alpha(i)/G alpha(o) subunits, combined with a suppression of other GTPases, primarily G alpha(s). However, the GTPgammaS binding data show that the peptides retain some of the activating property even in PTX-treated cell membranes. In conclusion, the conjugation of mastoparan with the V1a receptor antagonists produce peptides with properties different from the parent peptides that could be used to elucidate the role of different G proteins in insulin release.

Animals↗

PubMed1999

Different modes of action of the imidazoline compound RX871024 in pancreatic beta-cells. Blocking of K+ channels, mobilization of Ca2+ from endoplasmic reticulum, and interaction with exocytotic machinery.

The imidazoline compound RX871024 glucose-dependently potentiates the release of insulin in pancreatic islets and beta-cell lines. This activity of the compound is not related to its action by stimulating alpha 2-adrenoceptors and I1- and I2-imidazoline receptors. There are at least three modes of action of RX871024 in beta-cells: (1) RX871024 blocks the ATP-dependent, Ca(2+)-activated, and delayed rectifier K+ channel activity; (2) RX871024 causes mobilization of Ca2+ from thapsigargin-sensitive intracellular stores, the effect probably controlled by cytochrome P450; and (3) the stimulatory activity of RX871024 on insulin release involves interaction of the compound with the exocytotic machinery, unrelated to the changes in membrane potential and cytoplasmic-free Ca2+ concentration, whereas protein phosphorylation plays an important role in this process. The maximal insulinotropic effect of RX871024 is much higher than that of the sulfonylurea glibenclamide. RX871024 stimulates insulin release and normalizes blood glucose levels in rats in vivo without affecting blood pressure and heart rate.

Animals↗

PubMed1999

[Gastrointestinal peptides among new therapeutic agents used in type 2 diabetes].

The pharmacological arsenal available today for the treatment of type II diabetes is often insufficient to allow optimal control of the disease. Each agent corrects only one or a few of the multiple defects that characterise type II diabetes. Currently, new drugs are under development that target several of the clinical abnormalities. These agents include the gastrointestinal peptides, glucagon-like polypeptide-1 (GLP-1) and amylin, and their analogues. New rapid- and long-acting insulin analogues will also constitute interesting treatment alternatives.

Diabetes Mellitus, Type 2↗

PubMed1999

Molecular cloning of a full-length cDNA for human type 3 adenylyl cyclase and its expression in human islets.

The GK (Goto-Kakizaki) rat is a lean model of type 2 diabetes in which the diabetic state was spontaneously induced. We recently demonstrated the presence in GK rats of two functional point mutations in the promoter region of the type 3 adenylyl cyclase (AC3) gene that resulted in overexpression of AC3 mRNA associated with increased cAMP generation. The AC3 gene promoter mutations are the first molecular changes to be described in any specific gene in the GK rat. Here we report cloning of a full-length cDNA encoding human AC3 from a human fetal brain cDNA library using a PCR-based screening method. This 4142-bp cDNA predicts an open reading frame encoding 1144 amino acids containing putative 12 transmembrane-spanning domains which are typically found in other mammalian AC isoforms. Comparison of the translated amino acid sequence of the AC3 gene between human and rat shows 95% homology. Using RT-PCR, clear AC3 expression was detected in isolated human islets as well as a cDNA panel containing templates from eight different tissues (brain, heart, kidney, liver, lung, pancreas, placenta, and skeletal muscle). This wide distribution of AC3 expression may involve a number of physiological and pathophysiological metabolic processes.

Adenylyl Cyclases↗

PubMed1999

[Treatment of type 2 diabetes. Early detection of secondary oral treatment failure is important].

As type II diabetes is caused by decreased insulin secretion and increased insulin resistance, treatment must be aimed at the correction of these abnormalities. To this end, oral hypoglycaemic agents (OHAs) are used once adverse lifestyle factors have been suitably modified. New OHAs are being developed, or have already been approved. Subsequent treatment failure, after an initially satisfactory response, occurs in 5-10 per cent of patients on OHAs, and is currently treated with a combination of an OHA for daytime use and NPH insulin (isophane insulin) for use at bedtime. This yields metabolic control at least as good as that obtained with intensive insulin treatment, and at less risk of weight gain.

Administration, Oral↗

PubMed1999

Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects.

We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35-54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels > 11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8-11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1-8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2-2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels < 3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1-1.7 and 1.3, confidence interval 1.1-1.6 for concentrations 4.8-5.7 mmol/l and 5.8-7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI > 25.0 kg/m2) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3-177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population.

Adult↗

PubMed1999

In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7-36) amide in the rat studied by gamma camera.

The in vivo distribution of glucagon-like peptide-1 (7-36) amide (GLP-1) was studied in a rat model using radiolabeled GLP-1 (131I-GLP-1) depicted by a gamma-camera. The dynamic scan showed a rapid clearance from the blood circulation after an intravenous (i.v.) injection of 131I-GLP-1. After 10 min, the major part of the radioactivity was accumulated in the kidneys, whereas about 9% (of the blood value) was found in the brain. The pharmacokinetic study using 125I-GLP-1 demonstrated a rapid elimination from plasma, with a half-life of 3.3 +/- 0.6 min, a clearance of 117 +/- 15 mL/min, and a distribution volume of 557 +/- 61 mL. The elimination half-lives for the intact 125I-GLP-1 in lungs and kidneys were determined to 3.7 and 3.9 min, respectively. The metabolite GLP-1 (9-36) amide was followed in blood, lung, and kidney. All other organs assumed to contain low molecular weight fragments of GLP-1. The present study suggest that GLP-1 and/or its labeled metabolites cross the blood-brain barrier. Also the kidney plays an essential role in GLP-1 elimination after an i.v. administration, which can be of clinical interest especially in patients with kidney insufficiency who are treated with GLP-1.

Animals↗

PubMed1999

Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat.

Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6-8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D, were reduced by 20-35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, were increased by 40-50%. Neutral alpha-glucosidase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal alpha-glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.

Acarbose↗

PubMed1999

Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting.

Contributions of renal glucose production to whole-body glucose turnover were determined in healthy individuals by using the arteriovenous balance technique across the kidneys and the splanchnic area combined with intravenous infusion of [U-13C6]glucose, [3-(3)H]glucose, or [6-(3)H]glucose. In the postabsorptive state, the rate of glucose appearance was 11.5 +/- 0.6 micromol x kg(-1) x min(-1). Hepatic glucose production, calculated as the sum of net glucose output (9.8 +/- 0.8 micromol x kg(-1) x min(-1)) and splanchnic glucose uptake (2.2 +/- 0.3 micromol x kg(-1) x min(-1)) accounted for the entire rate of glucose appearance. There was no net exchange of glucose across the kidney and no significant renal extraction of labeled glucose. The renal contribution to total glucose production calculated from the arterial, hepatic, and renal venous 13C-enrichments (glucose M+6) was 5 +/- 2%. In the 60-h fasted state, the rate of glucose appearance was 8.2 +/- 0.3 micromol x kg(-1) x min(-1). Hepatic glucose production, estimated as net splanchnic output (5.8 +/- 0.7 micromol x kg(-1) x min(-1)) plus splanchnic uptake (0.6 +/- 0.3 micromol x kg(-1) x min(-1)) accounted for 79% of the rate of glucose appearance. There was a significant net renal output of glucose (0.9 +/- 0.3 micromol x kg(-1) x min(-1)), but no significant extraction of labeled glucose across the kidney. The renal contribution to whole-body glucose turnover calculated from the 13C-enrichments was 24 +/- 3%. We concluded that 1) glucose production by the human kidney in the postabsorptive state, in contrast to recent reports, makes at most only a minor contribution (approximately 5%) to blood glucose homeostasis, but that 2) after 60-h of fasting, renal glucose production may account for 20-25% of whole-body glucose turnover.

Adult↗

PubMed1999

Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.

To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.

3-O-Methylglucose↗

PubMed1999

Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs.

To determine whether glucagon-like peptide (GLP)-1 increases insulin sensitivity in addition to stimulating insulin secretion, we studied totally depancreatized dogs to eliminate GLP-1's incretin effect. Somatostatin was infused (0.8 microg x kg(-1) x min(-1)) to inhibit extrapancreatic glucagon in dogs, and basal glucagon was restored by intraportal infusion (0.65 ng x kg(-1) x min(-1)). To simulate the residual intraportal insulin secretion in type 2 diabetes, basal intraportal insulin infusion was given to obtain plasma glucose concentrations of approximately 10 mmol/l. Glucose was clamped at this level for the remainder of the experiment, which included peripheral insulin infusion (high dose, 5.4 pmol x kg(-1) x min(-1), or low dose, 0.75 pmol x kg(-1) x min(-1)) with or without GLP-1(7-36) amide (1.5 pmol x kg(-1) x min(-1)). Glucose production and utilization were measured with 3-[3H]glucose, using radiolabeled glucose infusates. In 12 paired experiments with six dogs at the high insulin dose, GLP-1 infusion resulted in higher glucose requirements than saline (60.9+/-11.0 vs. 43.6+/-8.3 micromol x kg(-1) x min(-1), P< 0.001), because of greater glucose utilization (72.6+/-11.0 vs. 56.8+/-9.7 micromol x kg(-1) x min(-1), P<0.001), whereas the suppression of glucose production was not affected by GLP-1. Free fatty acids (FFAs) were significantly lower with GLP-1 than saline (375.3+/-103.0 vs. 524.4+/-101.1 micromol/l, P<0.01), as was glycerol (77.9+/-17.5 vs. 125.6+/-51.8 micromol/l, P<0.05). GLP-1 receptor gene expression was found using reverse transcriptase-polymerase chain reaction of poly(A)-selected RNA in muscle and adipose tissue, but not in liver. Low levels of GLP-1 receptor gene expression were also found in adipose tissue using Northern blotting. In 10 paired experiments with five dogs at the low insulin dose, GLP-1 infusion did not affect glucose utilization or FFA and glycerol suppression when compared with saline, suggesting that GLP-1's effect on insulin action was dependent on the insulin dose. In conclusion, in depancreatized dogs, GLP-1 potentiates insulin-stimulated glucose utilization, an effect that might be contributed in part by GLP-1 potentiation of insulin's antilipolytic action.

Adipose Tissue↗

PubMed1999

Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men.

OBJECTIVE: To investigate the association between low birth weight and glucose intolerance in relation to family history of diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cross-sectional study of 2,237 men born in 1938-1957 in four municipalities in the outskirts of Stockholm, 50% of whom had a family history of diabetes (at least one first-degree or two second-degree relatives with diabetes). Oral glucose tolerance testing detected 35 cases of type 2 diabetes, 102 cases of impaired glucose tolerance, and 57 cases of impaired fasting glucose. RESULTS: In subjects without a family history of diabetes, low (< or = 3,000 g) birth weight was associated with an odds ratio of 2.3 (95% confidence intervals = 0.4-14.4) for diabetes, 1.8 (0.7-4.3) for impaired glucose tolerance, and 3.3 (1.0-10.4) for impaired fasting glucose. In subjects with a family history of diabetes, the corresponding figures were approximately similar, except for diabetes, for which the odds ratio was 5.4 (2.0-14.9). For men with low birth weight in combination with a family history of diabetes, the odds ratio was 10.9 (2.9-41.2) for diabetes, 2.4 (1.1-5.6) for impaired glucose tolerance, and 5.9 (2.1-16.3) for impaired fasting glucose. CONCLUSIONS: This study indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. This finding was most pronounced in subjects with diabetes in the family, but it was also indicated in those without a family history of diabetes. Men with the combination of low birth weight and family history of diabetes seem to be at particularly high risk of developing type 2 diabetes.

Adult↗

PubMed1998

Weight history, glucose intolerance, and insulin levels in middle-aged Swedish men.

The association between weight history and glucose intolerance was examined in a cross-sectional study consisting of 3,128 Swedish men aged 35-56 years, 52 percent of whom had a family background of diabetes mellitus. Oral glucose tolerance testing detected 55 cases of type 2 (non-insulin-dependent) diabetes and 172 cases of impaired glucose tolerance. Among men with no family history of diabetes, the estimated odds ratios for impaired glucose tolerance associated with short (<5 years) and long (> or =10 years) durations of obesity (body mass index (weight (kg)/height2 (m2) > or =25.0) were 1.3 (95% confidence interval (CI) 0.2-7.7) and 11.8 (95% CI 3.3-41.9), respectively. Among men with a family history of diabetes, the odds ratios were 2.0 (95% CI 0.8-4.7) and 4.0 (95% CI 1.8-9.1), respectively. Corresponding estimates of the odds of type 2 diabetes, adjusted for family history of diabetes, were 1.9 (95% CI 0.5-7.1) and 7.3 (95% CI 2.2-23.7), respectively. The odds of high (> or =30.0 mU/liter) fasting insulin levels in subjects with impaired glucose tolerance were 6.9 (95% CI 0.6-74.2) and 21.0 (95% CI 2.1-206.4) for short and long durations of obesity, respectively. Corresponding estimated odds of low 2-hour insulin response (< or =71.9 mU/liter) were 0.7 (95% CI 0.2-2.9) and 3.3 (95% CI 1.2-8.9). Homeostasis model assessment of insulin resistance yielded an odds ratio of 6.7 (95% CI 0.6-73.4) for a short duration of obesity and 20.0 (95% CI 2.0-200.6) for a long duration. Examination of beta-cell function with homeostasis model assessment resulted in odds ratios of 0.2 (95% CI 0.0-1.6) and 2.0 (95% CI 0.7-5.4) for short and long durations of obesity, respectively. These data indicate that obesity decreases glucose tolerance by way of progressively increased insulin resistance and, in the case of prolonged duration, by decreased insulin secretion as well.

Body Mass Index↗