Weight Loss, Lifestyle Intervention, and Metformin Affect Longitudinal Relationship of Insulin Secretion and Sensitivity

Arreola, Elsa Vazquez; Knowler, William C.; Hanson, Robert L.

doi:10.1210/clinem/dgac509

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…This is consistent with previous results that indicated that in people with increased diabetes risk (in this case carriers), the most important factor for delaying or preventing diabetes is the ability to reach glucose homeostasis by adequately compensating for decreased insulin sensitivity (insulin secretion compensation). 20 The variant associated significantly with the prevalence of retinopathy, but not with the other complications. R1420H carriers had a higher prevalence (but not significantly) of retinopathy even in observations without diabetes; signs of diabetic retinopathy have been previously found in people without diabetes in this population.…”

Section: Discussionmentioning

confidence: 87%

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Effects of theABCC8R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy

Vazquez Arreola,

Knowler,

Baier

et al. 2023

BMJ Open Diab Res Care

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IntroductionTheABCC8gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of anABCC8R1420H loss-of-function variant on beta-cell function, incidence of type 2 diabetes, and age-at-onset, prevalence, and progression of diabetes complications were assessed in a longitudinal study in American Indians.Research design and methodsWe analyzed beta-cell function through the relationship between insulin secretion and insulin sensitivity in members of this population without diabetes aged ≥5 years using standard major axis regression. We used hierarchical logistic regression models to study cross-sectional associations with diabetes complications including increased albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), and retinopathy. This study included 7675 individuals (254 variant carriers) previously genotyped for the R1420H with available phenotypic data and with a median follow-up time of 13.5 years (IQR 4.5–26.8).ResultsVariant carriers had worse beta-cell function than non-carriers (p=0.0004; on average estimated secretion was 22% lower, in carriers), in children and adults, with no difference in insulin sensitivity (p=0.50). At any body mass index and age before 35 years, carriers had higher type 2 diabetes incidence. This variant did not associate with prevalence of increased albuminuria (OR 0.87, 95% CI 0.66 to 1.16), severe albuminuria (OR 0.96, 95% CI 0.55 to 1.68), or reduced eGFR (OR 0.44, 95% CI 0.18 to 1.06). By contrast, the variant significantly associated with higher retinopathy prevalence (OR 1.74, 95% CI 1.19 to 2.53) and this association was only partially mediated (<11%) by glycemia, duration of diabetes, risk factors of retinopathy, or insulin use. Retinopathy prevalence in carriers was higher regardless of diabetes presence.ConclusionsTheABCC8R1420H variant is associated with increased risks of diabetes and of retinopathy, which may be partially explained by higher glycemia levels and worse beta-cell function.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Effects of theABCC8R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy

Vazquez Arreola,

Knowler,

Baier

et al. 2023

BMJ Open Diab Res Care

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“…In this work, we found elevated levels of arachidonic acid and its precursor, linoleic acid, in T2D subjects treated with diet and lifestyle modifications as compared to ND controls, with metformin therapy reversing these changes. While we did not directly measure β-cell function in our study, others have found metformin augments insulin secretion, even in the context of reduced insulin demand (Vazquez Arreola et al, 2022). Therefore, it is possible decreased β-cell PGE2 is at least partially responsible for metformin's effects.…”

Section: Improved Pancreatic β-Cell Function May Occur With Metformin...mentioning

confidence: 80%

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort

Wancewicz

Zhu

Fenske

et al. 2023

J Pharmacol Exp Ther

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Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to nondiabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement:This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

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“…Metformin is one of the most commonly used oral antidiabetic agents in treating type 2 diabetes, and it can also be used in prediabetic individuals to retard diabetes progression. Some studies demonstrate that metformin positively affects weight loss due to its mechanism, and some demonstrate a neutral effect 6 . In overweight and obese diabetic patients, 5–10% weight loss improves glycemic control and reduces the need for antidiabetic drugs 7 ., although providing weight loss is problematic in diabetic patients due to polypharmacy, weight gain side effects of drugs, and glycemic fluctuations 8 .…”

Section: Introductionmentioning

confidence: 99%

Comparison of orlistat and orlistat plus metformin therapy between diabetic and nondiabetic groups

Kişioğlu

Karakullukçu

Tufekci

et al. 2023

Rev. Assoc. Med. Bras.

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SUMMARY OBJECTIVE: The objective of this study was to examine the effects of orlistat use on metabolic control and weight loss in diabetic and nondiabetic patients. METHODS: A total of 119 patients with body mass index≥40 kg/m 2 and receiving orlistat therapy, who applied to the Endocrinology polyclinic between January 2016 and October 2019, were included. The patients’ weight changes and biochemical values (i.e., fasting glucose, HbA1c, ALT, creatinine, and lipid parameters) were evaluated at the drug beginning and the last polyclinic control. The patients were divided into groups, whether they had diabetes or used metformin, and compared. RESULTS: The mean age of the 119 patients in the study was 45.3±11.5 years. A total of 94.1% of the patients were females and 5.9% were males. A total of 38.7% of the patients had diabetes and 29.4% had prediabetes. When the patients were compared to whether they had diabetes or used metformin, there was a statistically significant difference between the groups according to weight loss. The mean weight change of patients without diabetes and receiving metformin and orlistat was statistically significantly higher than that of patients with diabetes and receiving metformin and orlistat. DISCUSSION: It was determined that the weight loss effect of orlistat in obesity was seen in all groups, but this effect decreased in the diabetic group.

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Weight Loss, Lifestyle Intervention, and Metformin Affect Longitudinal Relationship of Insulin Secretion and Sensitivity

Cited by 4 publications

References 23 publications

Effects of theABCC8R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy

Effects of theABCC8R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort

Comparison of orlistat and orlistat plus metformin therapy between diabetic and nondiabetic groups

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