Aim
To gain further insights into the efficacy of SAR425899, a dual glucagon‐like peptide‐1/glucagon receptor agonist, by providing direct comparison with the glucagon‐like peptide‐1 receptor ...agonist, liraglutide, in terms of key outcomes of glucose metabolism.
Research Design and Methods
Seventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once‐daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods.
Results
From BSL to EOT (median 25th, 75th percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% 21%, 74%), while secretion enhanced both in SAR425899 (125% 63%, 228%) and liraglutide (73% 43%, 147%). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% 58%, 440% and 36% 21%, 197%), basal beta‐cell responsiveness (67% 34%, 112% and 40% 16%, 59%), and above‐basal beta‐cell responsiveness (139% 64%, 261% and 69% −15%, 120%). A significant delay in glucose absorption was highlighted in SAR425899 (37% 52%,18%).
Conclusions
SAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in beta‐cell function was shown by SAR425899 than liraglutide.
Aims
Insulin deficiency (ID) and resistance (IR) contribute to progression from normal glucose tolerance to diabetes to insulin requirement although their relative contributions in young‐onset ...diabetes is unknown.
Methods
We examined the associations of HOMA2 using fasting plasma glucose and C‐peptide in Chinese aged 20–50 years with (1) progression to type 2 diabetes (T2D) in participants without diabetes in a community‐based cohort (1998–2013) and (2) glycaemic deterioration in patients with T2D in a clinic‐based cohort (1995–2014). We defined ID as HOMA2‐%B below median and insulin IR as HOMA2‐IR above median.
Results
During 10‐year follow‐up, 62 (17.9%) of 347 community‐dwelling participants progressed to T2D. After 8.6 years, 291 (48.1%) of 609 patients with T2D had glycaemic deterioration. At baseline, progressors for T2D had higher HOMA2‐IR, while in patients with T2D, progressors for glycaemic deterioration had higher HOMA2‐IR and lower HOMA2‐%B than non‐progressors. The non‐ID/IR group and the ID/IR group had an adjusted odds ratios of 2.47 (95% CI: 1.28, 4.94) and 5.36 (2.26, 12.79), respectively, for incident T2D versus the ID/non‐IR group. In patients with T2D, 50% of the ID/IR group required insulin at 6.7 years versus around 11 years in the non‐ID/IR or ID/non‐IR, and more than 15 years in the non‐ID/non‐IR group. Compared with the latter group, the adjusted hazard ratios were 2.74 (1.80, 4.16) in the ID/non‐IR, 2.73 (1.78, 4.19) in the non‐ID/IR and 4.46 (2.87, 6.91) in the ID/IR group (p‐interaction = 0.049).
Conclusions
In young Chinese adults, IR and ID contributed to progression to T2D and glycaemic deterioration.
•Chronic pancreatitis is the most frequent cause of diabetes secondary to pancreatic disease.•Alterations in insulin secretion can only be detected by comparisons within the same glucose tolerance ...range.•Chronic pancreatitis does not induce specific alterations of insulin secretion.•Diabetes with chronic pancreatitis presents a reduced functional beta-cell mass.
Chronic pancreatitis (CP) is – along with acute pancreatitis - the most frequent cause of diabetes of the exocrine pancreas (DEP). Although insulin deficiency is widely accepted as the major feature of DEP, it is still unclear whether diabetes associated with CP is characterized by additional or different functional defects of the insulin secretory machinery. To identify possible functional defects specifically induced by CP, we performed a cross-sectional study in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) comparing patients with and without CP (CP vs. NCP).
We administered an oral glucose tolerance test (OGTT) to all participants and, according to their glucose tolerance, classified them as NGT, IGT and DM. Insulin sensitivity and beta-cell functional parameters were derived from OGTT, hyperglycemic clamp and hyperinsulinemic euglycemic clamp.
Studying 146 subjects, we found that beta-cell function and insulin secretion were significantly lower in CP compared to NCP patients. However, when we classified the subjects according to OGTT-derived glucose tolerance, we found no differences in beta-cell function or in insulin sensitivity between CP and NCP with the same glucose tolerance status. Of note, we found that arginine-stimulated insulin secretion is reduced only in subjects with CP and DM compared to NCP subjects with DM.
Patients with CP had no specific alterations in insulin secretion and beta-cell function. However, in patients diagnosed with diabetes, we found a lower arginine-stimulated insulin secretion, a marker of reduced functional mass.
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Aim
To test the hypothesis that the addition of periodic courses of short‐term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of ...beta‐cell function following induction IIT.
Methods
In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years’ duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2‐week courses of IIT every 3 months for 2 years. Beta‐cell function was assessed by the Insulin Secretion Sensitivity Index‐2 (ISSI‐2) at an oral glucose tolerance test every 3 months.
Results
In both arms, induction IIT increased ISSI‐2, improved whole‐body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline‐adjusted ISSI‐2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline‐adjusted difference −35 95% CI: −66, –3), with three additional beta‐cell measures showing no significant differences. Baseline‐adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years.
Conclusion
Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta‐cell function.
Aim
To present an overview of exendin(9‐39)NH2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes.
Methods
We systematically searched the literature on ...exendin(9‐39)NH2 and included for review 44 clinical studies reporting use of exendin(9‐39)NH2 in humans.
Results
Exendin(9‐39)NH2 binds to the orthosteric binding site of the glucagon‐like peptide‐1 (GLP‐1) receptor with high affinity. The plasma elimination half‐life of exendin(9‐39)NH2 after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady‐state plasma concentrations can be expected. Studies utilizing infusions with exendin(9‐39)NH2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30‐900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9‐39)NH2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C‐peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9‐39)NH2 induces secretion of all L cell products (ie, in addition to GLP‐1, also peptide YY, glucagon‐like peptide‐2, oxyntomodulin, and glicentin) complicating use of exendin(9‐39)NH2 as a tool to study the isolated effect of GLP‐1.
Conclusions
Exendin(9‐39)NH2 is selective for the GLP‐1 receptor, with numerous and complex whole‐body effects. To obtain GLP‐1 receptor blockade in humans, we recommend an initial high‐dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9‐39)NH2 to GLP‐1 of 2000:1.
Highlights
Exendin(9‐39)NH2 is a competitive antagonist of the human GLP‐1 receptor.
Exendin(9‐39)NH2 has been used as a tool to delineate human GLP‐1 physiology since 1998.
Exendin(9‐39)NH2 induces secretion of GLP‐1 and other L cell products.
Reported effects of exendin(9‐39)NH2 on insulin levels and food intake are inconsistent.
Here, we provide recommendations for the use of exendin(9‐39)NH2 in clinical studies.
Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes ...(T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes.
Thirty individuals with T2D (age 18–75 years, BMI 27–50 kg m−2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR.
Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01).
VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management.
Aim
To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups.
Methods
The intrahepatic fat content ...(HFF%) was quantified by magnetic resonance imaging in a multi‐ethnic cohort of 632 obese youths aged 7‐18 years at baseline and after a 2‐year follow‐up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C‐peptide data during 3‐hour, 9‐point oral glucose tolerance tests.
Results
African American youths exhibited the lowest HFF% and a prevalence of non‐alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose‐stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group‐specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist‐hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow‐up was associated with decreased EIC and increased HIRI across all groups.
Conclusions
Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.
Aim
To evaluate the change in insulin sensitivity, β‐cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon‐like peptide‐1 ...receptor/glucagon receptor agonist, versus placebo.
Materials and Methods
Thirty‐six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low‐dose SAR425899 (0.03, 0.06 and 0.09 mg) and high‐dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day −1) and on days 1 and 28. Oral glucose and C‐peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β‐cell responsiveness and glucose absorption.
Results
With low‐dose SAR425899, high‐dose SAR425899 and placebo, β‐cell function from day −1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was −32%, −20% and 8%, respectively.
Conclusions
After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β‐cell function and slowing glucose absorption rate.
Glucokinase, which phosphorylates glucose to form glucose‐6‐phosphate, plays a critical role in regulating blood glucose levels. On the basis of data of glucokinase‐knockout and transgenic mice and ...humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycaemia in patients with diabetes. In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. However, some have been discontinued because of efficacy and safety issues. One of these issues is loss of the drug's efficacy over time. This unsustained glycaemic efficacy may be associated with the excess glycolysis by glucokinase activation in pancreatic beta cells, resulting in beta‐cell failure. Recently, we have shown that glucokinase haploinsufficiency ameliorated glucose intolerance by increasing beta‐cell function and mass in a mouse model of diabetes. Given that a similar phenotype has been observed in glucokinase‐activated beta cells and diabetic beta cells, glucokinase inactivation may be a new therapeutic target for type 2 diabetes.
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