High insulin — is it more harmful than sugar?

Aim of the study: Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.

Results: Based on data from these studies, including 310,819 participants and 15,043 cases of type 2 diabetes, individuals in the highest quantile of SSB intake (most often 1-2 servings/day) had a 26% greater risk of developing type 2 diabetes than those in the lowest quantile (none or <1 serving/month) (relative risk [RR] 1.26 [95% CI 1.12-1.41]). Among studies evaluating metabolic syndrome, including 19,431 participants and 5,803 cases, the pooled RR was 1.20 [1.02-1.42]. In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.

Aim of the study: Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance.

Results: Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.

Aim of the study: Lifestyle factors conferring increased diabetes risk are associated with elevated basal insulin levels (hyperinsulinaemia). The latter predicts later obesity in children and adolescents.A causal role of hyperinsulinaemia for adipose tissue growth is probable because pharmacological reduction of insulin secretion lowers body weight in people who are obese.

Results: Genetic inactivation of insulin gene alleles in mice also lowers their systemic insulin levels and prevents or ameliorates high-fat diet-induced obesity. Hyperinsulinaemia causes weight gain because of a physiological property of insulin. Insulin levels that are on the high side of normal, or which are slightly elevated, are sufficient to suppress lipolysis and promote lipogenesis in adipocytes. The effect of insulin on glucose transport or hepatic glucose production requires six or two times higher hormone levels, respectively.It seems justified to suggest a lifestyle that avoids high insulin levels in order to limit anabolic fat tissue activity.

Aim of the study: Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established. Here we show that a protein kinase D2 (PRKD2) nonsense mutation (K410X) in two rhesus monkeys with extreme hyperinsulinemia along with IR and metabolic defects by using extreme phenotype sampling and deep sequencing analyses.

Results: This mutation reduces PRKD2 at both the mRNA and the protein levels. Taking advantage of a PRKD2-KO mouse model, we demonstrate that PRKD2 deletion triggers hyperinsulinemia which precedes to IR and metabolic disorders in the PRKD2 ablation mice. PRKD2 deficiency promotes β-cell insulin secretion by increasing the expression and activity of L-type Ca2+ channels and subsequently augmenting high glucose- and membrane depolarization-induced Ca2+ influx. Altogether, these results indicate that down-regulation of PRKD2 is involved in the pathogenesis of hyperinsulinemia which, in turn, results in IR and metabolic disorders.

Aim of the study: The effect of diet on insulin resistance (IR) in polycystic ovary syndrome (PCOS) is controversial. Thus, we conducted this systematic review and meta-analysis to evaluate whether diet could reduce IR in women with PCOS while providing optimal and precise nutrition advice for clinical practice.

Results: A total of 19 trials (1193 participants) were included. The analysis showed that diet was significantly related to improvements in IR and body composition (eg, homeostasis model assessment of insulin resistance, fasting insulin, fasting plasma glucose, body mass index [BMI], weight, and waist circumference) in PCOS patients. The Dietary Approaches to Stop Hypertension diet and calorie-restricted diets might be the optimal choices for reducing IR and improving body composition, respectively, in the PCOS population. Additionally, the effects were associated with the course of treatment. The longer the duration, the greater the improvement was. Compared with metformin, diet was also advantageous for weight loss (including BMI and weight) and had the same effects on insulin regulation. Overall, our findings suggest that diet is an effective, acceptable and safe intervention for relieving IR, and professional dietary advice should be offered to all PCOS patients.

Aim of the study: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among individuals with type 2 diabetes mellitus (T2DM), largely due to shared metabolic risk factors such as insulin resistance and obesity. This study aimed to examine the associations between these indices and the likelihood of MASLD in adults with T2DM.

Results: Lifestyle, and metabolic variables, the odds ratio for MASLD in the highest EDIR quartile was 7.81 (p = 0.001), and for ELIH it was 8 (p < 0.001), and it was 3.21 (p = 0.032) for ELIR. No significant associations were observed for EDIH. Dietary and lifestyle patterns with greater insulinemic potential may contribute to MASLD risk in individuals with T2DM. These findings highlight the importance of insulin-modulating dietary strategies in the prevention and management of liver complications in this high-risk population.

Aim of the study: To evaluate bexagliflozin for insulin control in horses with naturally occurring insulin dysregulation.

Results: Mean resting, maximal (Cmax), and area under the curve (AUC) insulin were lower after BEXA06 (resting, 17.6 μIU/mL [95% CI, 5.3 to 29.9 μIU/mL]; Cmax, 48.4 μIU/mL [95% CI, 24.0 to 72.8 μIU/mL]; AUC, 4,084.0 μIU/mL*min [95% CI, 1,944.4 to 6,223.5 μIU/mL*min]) compared to placebo control (resting, 53.9 μIU/mL [95% CI, 35.0 to 72.7 μIU/mL]; Cmax, 90.9 μIU/mL [95% CI, 65.0 to 116.9 μIU/mL]; AUC, 9,146.3 μIU/mL*min [95% CI, 6,428.9 to 11,863.7 μIU/mL*min]), but not after BEXA03. Mild hypertriglyceridemia was observed in some horses following treatment with BEXA06 (n = 5), but mean resting triglyceride concentrations were not significantly higher for BEXA06 (49 mg/dL; 95% CI, 30 to 67 mg/dL) compared to the untreated control (32 mg/dL; 95% CI, 26 to 38 mg/dL). Bexagliflozin (0.06 mg/kg, PO, q 24 h) controlled insulin with minimal impact on serum triglycerides in Arabian horses with naturally occurring insulin dysregulation.

Aim of the study: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are promising drugs for treatment of hyperinsulinemia in insulin-dysregulated (ID) horses. Compare short-term effects of the SGLT2 inhibitor canagliflozin versus placebo on glucose and insulin responses during an oral sugar test (OST) and a forage-based feed challenge test (FCT), and to assess adverse effects.

Results: Peak insulin concentrations (μIU/mL) during the OST and the FCT were lower after treatment with canagliflozin 0.6 and 1.2 mg/kg compared with placebo (P ≤ .01); OST: 122.0 (96.6-154.0) and 108.6 (85.6-137.8) vs 288.7 (227.1-366.9) and FCT: 78.3 (37.6-162.9) and 54.2 (25.7-114.5) vs 140.3 (68.5-287.3). Canagliflozin caused a dose-dependent increase in triglyceride concentrations (P ≤ .01). Post-treatment triglyceride concentrations were 0.5 (0.4-0.8), 1.3 (0.9-2.0), and 2.9 (1.9-4.4) mmol/L for placebo, 0.6 mg/kg, and 1.2 mg/kg groups, respectively. Canagliflozin effectively decreases hyperinsulinemia in ID horses but induces a dose-dependent increase in triglyceride concentrations.