Advances in small-molecule insulin secretagogues for diabetes treatment.

Diabetes, a metabolic disease caused by abnormally high levels of blood glucose, has a high prevalence rate worldwide and causes a series of complications, including coronary heart disease, stroke, peripheral vascular disease, end-stage renal disease, and retinopathy. Small-molecule compounds have been developed as drugs for the treatment of diabetes because of their oral advantages. Insulin secretagogues are a class of small-molecule drugs used to treat diabetes, and include sulfonylureas, non-sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and other novel small-molecule insulin secretagogues. However, many small-molecule compounds cause different side effects, posing huge challenges to drug monotherapy and drug selection. Therefore, the use of different small-molecule drugs must be improved. This article reviews the mechanism, advantages, limitations, and potential risks of small-molecule insulin secretagogues to provide future research directions on small-molecule drugs for the treatment of diabetes.

Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years.

Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for studies evaluating associations between diabetes medications and the risk of breast, lung, colorectal, prostate, liver, and pancreatic cancers. A total of 92 studies (3 randomized controlled trials, 64 cohort studies, and 25 case-control studies) were identified in the systematic review, involving 171 million participants. Inverse relationships with colorectal (n = 18; RR = 0.85; 95% CI = 0.78-0.92) and liver cancers (n = 10; RR = 0.55; 95% CI = 0.46-0.66) were observed in biguanide users. Thiazolidinediones were associated with lower risks of breast (n = 6; RR = 0.87; 95% CI = 0.80-0.95), lung (n = 6; RR = 0.77; 95% CI = 0.61-0.96) and liver (n = 8; RR = 0.83; 95% CI = 0.72-0.95) cancers. Insulins were negatively associated with breast (n = 15; RR = 0.90; 95% CI = 0.82-0.98) and prostate cancer risks (n = 7; RR = 0.74; 95% CI = 0.56-0.98). Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01-1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08-2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08-5.36). Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.

Trans-palmitoleic acid, a dairy fat biomarker, stimulates insulin secretion and activates G protein-coupled receptors with a different mechanism from the cis isomer.

Dietary trans-palmitoleic acid (trans 16:1n-7, tPOA), a biomarker for high-fat dairy product intake, has been associated with a lower risk of type 2 diabetes mellitus (T2DM) in some cross-sectional and prospective epidemiological studies. Here, we investigated the insulin secretion-promoting activity of tPOA and compared them with the effects evoked by the cis-POA isomer (cPOA), an endogenous lipokine biosynthesized in the liver and adipose tissue, and found in some natural food sources. The debate about the positive and negative relationships of those two POA isomers with metabolic risk factors and the underlying mechanisms is still going on. Therefore, we examined the potency of both POA isomers to potentiate insulin secretion in murine and human pancreatic ß cell lines. We also investigated whether POA isomers activate G protein-coupled receptors proposed as potential targets for T2DM treatment. We show that tPOA and cPOA augment glucose-stimulated insulin secretion (GSIS) to a similar extent; however, their insulin secretagogue activity is associated with different signaling pathways. We also performed ligand docking and molecular dynamics simulations to predict the preferred orientation of POA isomers and the strength of association between those two fatty acids and GPR40, GPR55, GPR119, and GPR120 receptors. Overall, this study provides insight into the bioactivity of tPOA and cPOA toward selected GPCR functions, indicating them as targets responsible for the insulin secretagogue action of POA isomers. It reveals that both tPOA and cPOA may promote insulin secretion and subsequently regulate glucose homeostasis.

Glycemic control and diabetes complications across health status categories in older adults treated with insulin or insulin secretagogues: The Diabetes & Aging Study.

BACKGROUND: For older adults with type 2 diabetes (T2D) treated with insulin or sulfonylureas, Endocrine Society guideline recommends HbA1c between 7% to <7.5% for those in good health, 7.5% to <8% for those in intermediate health, and 8% to <8.5% for those in poor health. Our aim was to examine associations between attained HbA1c below, within (reference), or above recommended target range and risk of complication or mortality. METHODS: Retrospective cohort study of adults ≥65 years old with T2D treated with insulin or sulfonylureas from an integrated healthcare delivery system. Cox proportional hazards models of complications during 2019 were adjusted for sociodemographic and clinical variables. Primary outcome was a combined outcome of any microvascular or macrovascular event, severe hypoglycemia, or mortality during 12-month follow-up. RESULTS: Among 63,429 patients (mean age: 74.2 years, 46.8% women), 8773 (13.8%) experienced a complication. Complication risk was significantly elevated for patients in good health (n = 16,895) whose HbA1c was above (HR 1.97, 95% CI 1.62-2.41) or below (HR 1.29, 95% CI 1.02-1.63) compared to within recommended range. Among those in intermediate health (n = 30,129), complication risk was increased for those whose HbA1c was above (HR 1.45, 95% CI 1.30-1.60) but not those below the recommended range (HR 0.99, 95% CI 0.89-1.09). Among those in poor health (n = 16,405), complication risk was not significantly different for those whose HbA1c was below (HR 0.98, 95% CI 0.89-1.09) or above (HR 0.96, 95% CI 0.88-1.06) recommended range. CONCLUSIONS: For older adults with T2D in good health, HbA1c below or above the recommended range was associated with significantly elevated complication risk. However, for those in poor health, achieving specific HbA1c levels may not be helpful in reducing the risk of complications.