The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. OBJECTIVE To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.DESIGN, SETTING, AND PARTICIPANTS Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020 follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.INTERVENTIONS Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. MAIN OUTCOMES AND MEASURESThe primary end point was mean change from baseline in glycated hemoglobin A 1c (HbA 1c ) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA 1c levels. RESULTS Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA 1c , 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA 1c change from baseline was −2.40% with 10-mg tirzepatide and −2.34% with 15-mg tirzepatide vs −0.86% with placebo (10 mg: difference vs placebo, −1.53% [97.5% CI, −1.80% to −1.27%]; 15 mg: difference vs placebo, −1.47% [97.5% CI, −1.75% to −1.20%]; P < .001 for both). Mean HbA 1c change from baseline was −2.11% with 5-mg tirzepatide (difference vs placebo, −1.24% [95% CI, −1.48% to −1.01%]; P < .001]). Mean body weight change from baseline was −5.4 kg with 5-mg tirzepatide, −7.5 kg with 10-mg tirzepatide, −8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, −7.1 kg [95% CI, −8.7 to −5.4]; 10 mg: difference, −9.1 kg [95% CI, −10.7 to −7.5]; 15 mg: difference, −10.5 kg [95% CI, −12.1 to −8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA 1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.

Abstract-Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance. Key Words: angiotensin II Ⅲ insulin resistance Ⅲ oxidative stress Ⅲ glucose clamp technique Ⅲ sodium Ⅲ kinase S everal lines of evidence point to an association between hypertension and insulin resistance, 1,2 eg, hypertensive individuals are more likely to become diabetic than normotensive ones. 3 It is therefore notable that angiotensin II (AII) is reportedly involved in the development of both hypertension and insulin resistance, 4 -7 and agents that inhibit the action of AII, ie, angiotensin-converting enzyme inhibitors and type 1 AII (AT1) receptor antagonists, not only reduce blood pressure but also restore insulin sensitivity. 8 -14 It has been suggested that crosstalk between AII-and insulinsignaling pathways underlies AII-induced insulin resistance. According to that model, AII induces tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by Janus kinase 2 (JAK2) associated with the AT1 receptor, thereby attenuating insulin-induced activation of phosphatidylinositol (PI) 3-kinase associated with IRS-1, which in turn diminishes insulin sensitivity. 15,16 However, ...

Resistin is a hormone secreted by adipocytes that acts on skeletal muscle myocytes, hepatocytes, and adipocytes themselves, reducing their sensitivity to insulin. In the present study, we investigated how the expression of resistin is affected by glucose and by mediators known to affect insulin sensitivity, including insulin, dexamethasone, tumor necrosis factor-␣ (TNF-␣), epinephrine, and somatropin. We found that resistin expression in 3T3-L1 adipocytes was significantly upregulated by high glucose concentrations and was suppressed by insulin. Dexamethasone increased expression of both resistin mRNA and protein 2.5-to 3.5-fold in 3T3-L1 adipocytes and by ϳ70% in white adipose tissue from mice. In contrast, treatment with troglitazone, a thiazolidinedione antihyperglycemic agent, or TNF-␣ suppressed resistin expression by ϳ80%. Epinephrine and somatropin were both moderately inhibitory, reducing expression of both the transcript and the protein by 30 -50% in 3T3-L1 adipocytes. Taken together, these data make it clear that resistin expression is regulated by a variety of hormones and that cytokines are related to glucose metabolism. Furthermore, they suggest that these factors affect insulin sensitivity and fat tissue mass in part by altering the expression and eventual secretion of resistin from adipose cells.

Aims: This phase 3, 26-week, open-label, treat-to-target trial investigated the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in insulin-naïve Japanese adults with type 2 diabetes. Methods:Subjects were randomized to once-daily injections of IDegAsp (n = 147) or insulin glargine (IGlar) (n = 149), both ±≤2 oral antidiabetic treatments. IDegAsp was given before the largest meal at the discretion of each subject (and maintained throughout the trial); IGlar was dosed according to label. Both insulins were titrated to a target prebreakfast self-measured plasma glucose of 3.9 to <5.0 mmol/l. Conclusions: IDegAsp provided superior long-term glycaemic control compared to IGlar, with similar FPG and doses and numerically lower rates of overall and nocturnal hypoglycaemia (p = NS).