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Elevated plasma FFA cause [beta]-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or [DELTA]C-peptide/[DELTA]glucose AUC (+177%, P = 0.02), an index of improved [beta]-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 [+ or -] 5% (P < 0.04). First- (+19 [+ or -] 6%, P = 0.1) and second-phase (+31 [+ or -] 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 [+ or -] 7 (P < 0.05) and 41 [+ or -] 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ([r.sup.2] = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM. insulin resistance; lipotoxicity; [beta]-cell; family history of T2DM doi:10.1152/ajpendo.00624.2006.

A study to evaluate the efficacy of pioglitazone in the treatment of nonalcoholic steatohepatitis is conducted. Results confirm the effectiveness of pioglitazone as a form of treatment for nonalcoholic steatohepatitis and suggest further trials to assess the long-term benefits.

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (~1,500-4,000 [micro]mol/l). However, plasma FFA levels >1,000 [micro]mol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (~600-800 [micro]mol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [[3.sup.-3]H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ~1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal ([R.sub.d]) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in [R.sub.a] or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined. insulin resistance; free fatty acids; insulin signal transduction

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 [+ or -] 4 yr; body mass index, 27.4 [+ or -] 1.2 kg/[m.sup.2]; fasting plasma glucose, 5.2 [+ or -] 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU * [m.sup.-2] * [min.sup.-1]) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-[sup.3]H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance ([R.sub.d]). During the 3-h euglycemic insulin clamp before glucose ingestion, [R.sub.d] was decreased (8.8 [+ or -] 0.5 vs. 7.6 [+ or -] 0.5 mg * [kg.sup.-1] * [min.sup.-1], P < 0.01), and suppression of EGP was impaired (0.2 [+ or -] 0.04 vs. 0.07 [+ or -] 0.03 mg * [kg.sup.1] * [min.sup.-1] P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 [+ or -] 2 vs. 20 [+ or -] 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose [R.sub.d] and insulin-mediated suppression of EGP in healthy subjects but augments SGU. liver; oral glucose; skeletal muscle

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU * [kg.sup.-1] * [min.sup.-1]) clamp and a two-step euglycemic IGF-I (26 and 52 pmol * [kg.sup.-1] * [min.sup.-1]) clamp with [3-[sup.3]H]glucose, [1-[sup.14]C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal ([R.sub.d]) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of [R.sub.d] (second clamp step) in response to both insulin and IGF-I was reduced by ~40-50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin (P < 0.01-0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects (P < 0.05-0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I. insulin-like growth factor I; insulin resistance; free fatty acid metabolism; type 2 diabetes mellitus

Background: Whether the cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are comparable between White and Asian populations remains unclear.Purpose: To compare the cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between White and Asian populations and to compare the cardiorenal benefits between the two agents in Asian patients.Data Sources: Electronic databases were searched up to 28 March 2021.Study Selection: We included the cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors and GLP-1RAs where investigators reported major adverse CV events (MACE), CV death/hospitalization for heart failure (HHF), or composite renal outcomes with stratification by race.Data Extraction: We extracted the hazard ratio of each outcome stratified by race (Asian vs. White populations).Data Synthesis: In 10 SGLT2 inhibitor trials, there was no significant difference between Asian and White populations for MACE (P = 0.55), CV death/HHF (P = 0.87), or composite renal outcomes (P = 0.97). In seven GLP-1RA trials, we observed a similar MACE benefit between Asian and White populations (P = 0.10). In our networkmeta-analysis we found a comparable benefit for MACE between SGLT2 inhibitors and GLP-1RAs in Asian patients.Limitations: The data were from stratified analyses.Conclusions: There appear to be comparable cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between Asian and White participants enrolled in CV and renal outcome trials; the two therapies seem to have similar CV benefits for Asian participants. [ABSTRACT FROM AUTHOR]

Metabolic risk for cardiovascular and other systems includes much more than just LDL cholesterol. This JCL Roundtable brings together 3 experts to address new opportunities to reduce the risks posed by obesity, diabetes, and fatty liver disease. Successful nutritional approaches to weight loss are diverse and need to be matched with individual preferences. Topiramate plus extended-release phentermine has been shown to promote meaningful weight loss in randomized trials, but the patented drug combination is expensive. Clinical experience suggests that generic topiramate and phentermine may also be effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown favorable tolerability and efficacy for cardiovascular disease in randomized trials, an achievement without precedent among earlier diabetes medications. These 2 drug classes differ in their effects. GLP-1 RAs decrease atherosclerotic cardiovascular events and also decrease hemoglobin A1c, body weight, blood pressure, and possibly diabetic renal disease. SGLT2 inhibitors are effective in reducing heart failure events even among nondiabetic patients. They also decrease progression of diabetic renal disease. The presence of nonalcoholic fatty liver disease signifies risk for atherosclerotic cardiovascular disease as well as cirrhosis and serious hepatic decompensation, including hepatocellular carcinoma. The key to identifying cirrhosis risk is to assess pre-emptively liver fibrosis, which can be predicted initially with blood test risk scores (e.g., FIB-4 index) and more definitively by transient elastography and other imaging techniques and/or liver biopsy. Some medications approved for the treatment of type 2 diabetes may reduce liver fat (SGLT2 inhibitors, insulin) or even reverse steatohepatitis in paired liver biopsy studies (GLP-1 RAs or pioglitazone) Overall the field of preventive metabolic medicine is expanding. Clinical lipidologists should become familiar with recent advances. [ABSTRACT FROM AUTHOR]