Alpha- and beta-cell abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes

New recommendations for the use of glycated haemoglobin A1c (HbA1c) to diagnose prediabetes and type 2 diabetes have changed the constitution of the two populations. We aimed to investigate the pathophysiological characteristics of individuals with HbA1c-defined prediabetes and type 2 diabetes, respectively. Ten subjects with HbA1c-defined prediabetes, i.e. HbA1c from 5.7 to 6.4 % (39–46 mmol/mol), eight newly diagnosed patients with HbA1c-defined type 2 diabetes [HbA1c ≥6.5 % (≥48 mmol/mol)], and ten controls with HbA1c lower than 5.7 % (<39 mmol/mol), were studied. Blood was sampled over 4 h on two separate days after a 75 g-oral glucose tolerance test and an isoglycaemic intravenous glucose infusion, respectively. Blood was analysed for glucose, insulin, C-peptide, glucagon, and incretin hormones. Insulinogenic index, disposition index, glucagon suppression, and incretin effect were evaluated. Subjects with HbA1c-defined prediabetes showed significantly lower insulinogenic index (P = 0.02), disposition index (P = 0.001), and glucagon suppression compared with controls; and similar (P = NS) insulinogenic index and glucagon suppression and higher disposition index (P = 0.02) compared to HbA1c-diagnosed type 2 diabetic patients. The patients with type 2 diabetes showed lower insulinogenic index (P = 0.0003), disposition index (P < 0.0001), and glucagon suppression compared with the controls. The incretin effect was significantly (P < 0.05) reduced in patients with HbA1c-defined type 2 diabetes compared to subjects with HbA1c-defined prediabetes and controls. Plasma levels of incretin hormones were similar across the three groups. HbA1c associated negatively with insulinogenic index, disposition index, and incretin effect. Our findings show clear alpha- and beta-cell dysfunction in HbA1c-defined type 2 diabetes compatible with the previously described pathophysiology of plasma glucose-defined type 2 diabetes. Furthermore, in HbA1c-defined prediabetes, we show defective insulin response in combination with inappropriate suppression of glucagon, which may constitute new targets for pharmacological interventions.     

Kidney injury in cirrhosis: pathophysiological and therapeutic aspects of hepatorenal syndromes

Acute kidney injury (AKI) is frequent in patients with cirrhosis. AKI and hyponatraemia are major determinants of the poor prognosis in advanced cirrhosis. The hepatorenal syndrome (HRS) denotes a functional and potential reversible impairment of renal function. Type 1 HRS, a special type of AKI, is a rapidly progressive AKI, whereas the renal function in type 2 HRS decreases more slowly. HRS is precipitated by factors such as sepsis that aggravate the effective hypovolaemia in decompensated cirrhosis, by lowering arterial pressure and cardiac output and enhanced sympathetic nervous activity. Therefore, attempts to prevent and treat HRS should seek to improve liver function and to ameliorate arterial hypotension, central hypovolaemia and cardiac output, and to reduce renal vasoconstriction. Ample treatment of HRS is important to prevent further progression and death, but as medical treatment only modestly improves long‐term survival, these patients should always be considered for liver transplantation. Hyponatraemia, defined as serum sodium <130 mmol/L, is common in patients with decompensated cirrhosis. From a pathophysiological point of view, hyponatraemia is related to an impairment of renal solute‐free water excretion most likely caused by an increased vasopressin secretion. Patients with cirrhosis mainly develop hypervolaemic hyponatraemia. Current evidence does not support routine use of vaptans in the management of hyponatraemia in cirrhosis.     

Rifaximin has minor effects on bacterial composition,inflammation, and bacterial translocation in cirrhosis: A randomized trial

Background and Aim

Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo‐controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis.

Methods

Fifty‐four out‐patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end‐stage liver disease score 12 (± 3.9). Patients received rifaximin 550‐mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real‐time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing.

Results

Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell‐derived factor 1‐α, transforming growth factor β‐1, and high sensitivity C‐reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin.

Conclusion

Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).