The effects of macronutrients composition on hormones and substrates during a meal tolerance test in drug-naive and sitagliptin-treated individuals with type 2 diabetes: a randomized crossover study

ABSTRACT Objectives: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT). Materials and methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis. Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels. Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543

Disruption of glucose tolerance caused by glucocorticoid excess in rats is partially prevented, but not attenuated, by arjunolic acid.

Arjunolic acid (AA) obtained from plants of the Combretaceae family has shown anti-diabetic effects. Here, we analyzed whether the diabetogenic effects of dexamethasone (DEX) treatment on glucose homeostasis may be prevented or attenuated by the concomitant administration of AA. Adult Wistar rats were assigned to the following groups: vehicle-treated (Ctl), DEX-treated (1 mg/kg body weight intraperitoneally for 5 days) (Dex), AA-treated (30 mg/kg body weight by oral gavage twice per day) (Aa), AA treatment previous to and concomitant to DEX treatment (AaDex), and AA treatment after initiation of DEX treatment (DexAa). AA administration significantly ameliorated (AaDex) (P>0.05), but did not attenuate (DexAa), the glucose intolerance induced by DEX treatment. AA did not prevent or attenuate the elevation in hepatic glycogen and triacylglycerol content caused by DEX treatment. All DEX-treated rats exhibited hepatic steatosis that seemed to be more pronounced when associated with AA treatment given for a prolonged period (AaDex). Markers of liver function and oxidative stress were not significantly altered among the groups. Therefore, AA administered for a prolonged period partially prevents the glucose intolerance induced by DEX treatment, but it fails to produce this beneficial effect when given after initiation of GC treatment. Since AA may promote further hepatic steatosis when co-administered with GCs, care is required when considering this phytochemical as a hypoglycemiant and/or insulin-sensitizing agent.

Insulin signaling proteins in pancreatic islets of insulin-resistant rats induced by glucocorticoid

Chronic administration of glucocorticoids induces insulin resistance that is compensated by an increase in p-cell function and mass. Since insulin signaling is involved in the control of p-cell function and mass, we investigated the content of insulin pathway proteins in pancreatic islets. Rats were made insulin resistant by daily administration of dexamethasone (1mg/kg, b.w., i.p.) for 5 consecutive days (DEX), whilst control rats received saline (CTL). Circulating insulin and insulin released from isolated islets were measured by radioimmunoassay whereas the content of proteins was analyzed by Western blotting. DEX rats were hyperinsulinemic and exhibited augmented insulin secretion in response to glucose (P < 0.01). The IRa-subunit, IRS-1, Shc, AKT, p-p70S6K, ERK1/2, p-ERK1/2, and glucocorticoid receptor protein levels were similar between DEX and CTL islets. However, the IRp-subunit, p-IRp-subunit, IRS-2, PI3-K, p-AKT and p70S6K protein contents were increased in DEX islets (P < 0.05). We conclude that IRS-2 may have a major role, among the immediate substrates of the insulin receptor, to link activated receptors to downstream signaling components related to islet function and growth in this insulin-resistant rat model.

Efeitos da administração de dexametasona in vivo sobreglicemia, insulinemia e substratos circulantes sãodependentes do tempo de tratamento / Effects of dexamethasone administration in vivo on glycaemia, insulinaemia and circulating substrates are dependents of timeof treatment

Terapias a base de glicocorticóides estão freqüentemente associadas a alteração da sensibilidade à insulina. No presente trabalho avaliamos alguns parâmetros metabólicos como glicose, insulina, proteínas e colesterolplasmáticos em ratos tratados com dexametasona (DEX) (1mg/kg, peso corpóreo, ip.) por diferentes períodos de tempo (24h, 72h e 120h). Os ratos tratados com dexametasona apresentaram resistência periférica à insulina após 24h de administração da droga como indicam os valores de insulina plasmática de jejum (1,3 vs. 6,8 ng/ml para ratos controle [CTL] e DEX, respectivamente) e do índice HOMA. Resistência periférica à insulina adicional ocorre até o final do tratamento nos ratos DEX. A glicemia permanece moderadamente elevada até o período de 72h. Entretanto, observa-se marcante hiperglicemia após 120h (79 vs. 160 mg/dl para ratos CTL e DEX, respectivamente). Aumento significativo dos níveis de proteínas totais e albuminas plasmáticas ocorre a partir de 72h de tratamento e de colesterol total a partir de 120h. Glicogênio e gordura hepáticos aumentam de maneira tempo-dependente nos ratos DEX. Correlação negativa foi observada entre os valores de insulinemia de jejum e peso nos grupos tratados com dexametasona (r > 0,95). Portanto, administração de dexametasona, 1mg/kg, induz resistência periférica à insulina de maneira tempo-dependente a partir de 24h e aumento dos níveis circulantes de glicose e proteínas plasmáticos após 72h de tratamento.

Glucocorticoid therapies are often associated with insulin sensitivity alteration. In the present study we evaluated some metabolical parameters such as plasma glucose, insulin, protein and cholesterol levels in ratstreated with dexamethasone (DEX) (1mg/kg, body weight, ip.) in different periods (24h, 72h and 120h). Dexamethasonetreated rats show peripherical resistance after 24h of drug administration as indicated by the fasting plasma insulin values (1.3 vs.6.8 ng/ml for controls [CTL] and DEX rats, respectively) and by HOMA index. Additional peripheral insulin resistance occurred until the end of treatment in DEX rats. The glycaemia remained slightly elevated until 72h period. However, marked hyperglycaemia was observed after 120h (79 vs.160 mg/dl for CTL and DEX rats, respectively). Significantly increase of plasma albumin and total proteins levels occurred from 72h of treatment and total cholesterol from 120h. Hepatic glycogen and hepatic fat increased in a time-dependent manner in DEX rats. Negative correlation was observed between fasting insulin and body weight values in dexamethasone-treated groups (r > 0.95). Therefore, dexamethasone administration, 1mg/kg, induces insulin peripheral resistance in a time-dependent manner from 24h and increase of circulating plasma glucose and proteins levels after 72h of treatment.