Search

Objective: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).Research Design and Methods: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.Results: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role.Conclusions: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression. [ABSTRACT FROM AUTHOR]

Background: Roux-en-Y gastric bypass (RYGB) is a successful treatment for diabetes and obesity, possibly because it augments post-prandial secretion of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY). Subcutaneous infusion of GLP-1, OXM and PYY (GOP) mimicking hormone levels observed after RYGB reduces food intake. We hypothesized that GOP given for 4 weeks to patients with diabetes and obesity would improve glycaemia and body weight in comparison to placebo. Methods: 26 patients were randomized to a single-blinded GOP or Saline infusion. We also studied 21 patients who had RYGB, and 22 patients on a 800 kcal/day very low calorie diet (VLCD). Outcome measures were: (a) fructosamine levels; (b) body weight; (c) glucose and insulin during mixed meal test (MMT); (d) energy expenditure (EE); (e) energy intake (EI); (f) glucose variability. Findings: GOP infusion was well tolerated and led to a significantly greater mean reduction in fructosamine of -44·1 [95% CI 62·7, -25·5] µmol/L vs. Saline -11·7 [-18·9, -4·5] (difference in treatment effect 32·4 [12·9, 51·9], p=0·002). RYGB and VLCD also led to improvements (-34·0 [-45·6, -22.4] and -28·5 [-40.4, -16.7] respectively). The weight loss with GOP was -4·4 [-5·4, -3·5] kg compared to -2·5 [-4·1, -0·9] with Saline, -10·3 [-11·8, -8·8] with RYGB and -8·3 [-9·5, -7·1] with VLCD. Strikingly, there were key differences in glucose and insulin dynamics during the MMT. After RYGB there was an early glucose peak followed by marked insulin secretion, whereas GOP led to a flat euglycaemic response with no sharp insulin peak. The improvement in glucose tolerance with GOP was superior to VLCD. Interpretation: GOP infusion improves glycaemia and reduces body weight, supporting triple agonism of GLP-1, glucagon and peptide YY receptors as a treatment strategy for diabetes with obesity. Disclosure: P. Behary: None. G. Tharakan: None. K. Alexiadou: None. N.A. Johnson: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J. Cuenco: None. D. Hope: None. W. Dhillo: None. J.S. Minnion: None. G. Frost: Consultant; Self; Heptares, Nestlé. C. le Roux: Advisory Panel; Self; GI Dynamics, Inc., Herbalife International of America, Inc., Janssen Pharmaceuticals, Inc., Johnson & Johnson, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. S. Purkayastha: None. K. Moorthy: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. A. Ahmed: None. T. Prevost: None. S. Bloom: None. T.M.M. Tan: Other Relationship; Self; Novo Nordisk A/S. Funding: Medical Research Council UK; Imperial Biomedical Research Centre [ABSTRACT FROM AUTHOR]