Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. Methods.We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m 2 , HbA 1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.

Aims/Hypothesis: Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. Methods: We performed a twostep (1.5 and 6 pmol min −1 kg −1 ) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2 H 2 ]glucose and [ 2 H 5 ] glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. Results: In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48±12 vs 63±13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Conclusions/interpretation: Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [ 2 H 5 ]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating b-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting b-hydroxybutyrate levels rose from 246 6 288 to 561 6 596 mmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.When large quantities of glucose are pharmacologically forced into urinary excretion, whole-body metabolism undergoes adaptive changes involving glucose fluxes, hormonal responses, fuel selection, and energy expenditure (1,2). In previous work (3), we used empagliflozin to investigate the physiological response to forced glycosuria in patients with type 2 diabetes (T2D). By combining a mixed meal with the double-tracer technique, we found that after acute or chronic empagliflozin administration endogenous glucose production (EGP) rose, tissue glucose disposal (TGD) decreased, and lipid utilization increased. The aims of the present work were to measure the full spectrum of changes in lipolysis, lipid levels, and substrate availability consequent upon empagliflozininduced glycosuria in patients with T2D and to test whether and to what extent these changes occur in subjects without diabetes. RESEARCH DESIGN AND METHODS PopulationSixty-six patients with T2D were recruited into the study; their inclusion criteria are detailed in Ferrannini et al. (3). Twenty-five subjects without diabetes (12 with normal glucose tolerance [NGT] and 13 with impaired glucose tolerance [IGT]) served as control subjects (Supplementary Table 1). The glucose and hormone data for the patients with T2D have been reported (3) and are repeated here for comparison purposes. The study (clinicaltrials.gov identifier NCT01248364; EudraCT number 2010-...

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OBJECTIVE -To test the hypothesis that enzymes conventionally associated with liver dysfunction (aspartate aminotransferase, alanine aminotransferase, ␥-glutamyltransferase [GGT], and alkaline phosphatase) may predict diabetes. RESEARCH DESIGN AND METHODS-From a population-based diabetes survey, we selected 1,441 men and women in whom serum enzyme levels were Յ3 SDs of the mean population value, alcohol intake was Ͻ250 g/week, and hepatitis B and C virus testing was negative. At follow-up (7 years), 94 subjects developed diabetes and 93 impaired glucose tolerance (IGT).RESULTS -At baseline, all four enzymes were related to most of the features of the metabolic syndrome. After controlling for sex, age, adiposity/fat distribution, alcohol intake, serum lipids, and blood pressure, higher alanine aminotransferase and GGT values were significantly (P Ͻ 0.01) associated with both IGT and diabetes, whereas alkaline phosphatase was associated with diabetes only (P ϭ 0.0004) and aspartate aminotransferase with IGT only (P ϭ 0.0001). Raised GGT alone was associated with all the features of the metabolic syndrome. Raised GGT was a significant predictor of either IGT or diabetes (odds ratio 1.62 [95% CI 1.08 -2.42] top quartile vs. lower quartiles, P Ͻ 0.02) after controlling for sex, age, adiposity/fat distribution, alcohol consumption, fasting plasma insulin and proinsulin levels, and 2-h postglucose plasma glucose concentrations.CONCLUSIONS -Although mild elevations in liver enzymes are associated with features of the metabolic syndrome, only raised GGT is an independent predictor of deterioration of glucose tolerance to IGT or diabetes. As GGT signals oxidative stress, the association with diabetes may reflect both hepatic steatosis and enhanced oxidative stress. Diabetes Care 28:1757-1762, 2005A syndrome characterized by liver steatosis, lobular hepatitis, and chronically elevated serum alanine aminotransferase (ALT) concentrationstermed nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH), depending on the degree of parenchymal inflammation-has been identified in patients with negligible alcohol intake (1,2). These patients are often obese and dyslipidemic (3-6). In cross-sectional studies, NAFLD is associated with insulin resistance irrespective of BMI, fat distribution, and glucose tolerance (1,7,8). On these grounds, it has been suggested that hyperinsulinemia and insulin resistance may play a role in the pathogenesis of NAFLD (1) and that NAFLD is a feature of the metabolic syndrome (9).In a prospective study in Pima Indians, serum ALT concentrations were related to both hepatic insulin resistance and later decline in hepatic insulin sensitivity (10). In contrast, aspartate aminotransferase (AST) and ␥-glutamyltransferase (GGT) concentrations were unrelated to changes in hepatic insulin action (10). Based on previous findings (1,2), Vozarova et al. (10) suggested that a raised ALT reflects fatty changes in the liver and that this abnormality antedates the development of type 2 diabete...

The contribution of gluconeogenesis (GNG) to endogenous glucose output (EGO) in type 2 diabetes is controversial. Little information is available on the separate influence of obesity on GNG. We measured percent GNG (by the 2 H 2 O technique) and EGO (by 6,6-[ 2 H]glucose) in 37 type 2 diabetic subjects (9 lean and 28 obese, mean fasting plasma glucose [FPG] 8.3 ± 0.3 mmol/l) and 18 control subjects (6 lean and 12 obese) after a 15-h fast. Percent GNG averaged 47 ± 5% in lean control subjects and was significantly increased in association with both obesity (P < 0.01) and diabetes (P = 0.004). By multivariate analysis, percent GNG was independently associated with BMI (partial r = 0.27, P < 0.05, with a predicted increase of 0.9% per BMI unit) and FPG (partial r = 0.44, P = 0.0009, with a predicted increase of 2.7% per mmol/l of FPG). In contrast, EGO was increased in both lean and obese diabetic subjects (15.6 ± 0.5 µmol · min -1 · kg -1 of fat-free mass, n = 37, P = 0.002) but not in obese nondiabetic control subjects (13.1 ± 0.7, NS) as compared with lean control subjects (12.4 ± 1.4). Consequently, gluconeogenic flux (percent GNG ؋ EGO) was increased in obesity (P = 0.01) and markedly elevated in diabetic subjects (P = 0.0004), whereas glycogenolytic flux was reduced only in association with obesity (P = 0.05). Fasting plasma glucagon levels were significantly increased in diabetic subjects (P < 0.05) and positively related to EGO, whereas plasma insulin was higher in obese control subjects than lean control subjects (P = 0.05) and unrelated to measured glucose fluxes. We conclude that the percent contribution of GNG to glucose release after a 15-h fast is independently and quantitatively related to the degree of overweight and the severity of fasting hyperglycemia. In obese individuals, reduced glycogenolysis ensures a normal rate of glucose output. In diabetic individuals, hyperglucagonemia contributes to inappropriately elevated rates of glucose output from both GNG and glycogenolysis. Diabetes 49:1367-1373, 2000 P atients with type 2 diabetes typically show an increase in endogenous glucose output (EGO) (1-3). Several observations indicate that gluconeogenesis (GNG) is increased in type 2 diabetes. First, there is an increased protein turnover and hence release of gluconeogenic amino acids. Second, in obese patients with type 2 diabetes, the increased fat mass and rate of lipolysis contribute substrate (glycerol) (4,5) and activation (free fatty acids) (6,7) for GNG. Third, the net uptake of all gluconeogenic precursor substrates by the liver is increased. Using splanchnic catheterization, Felig et al. (8) estimated that in diabetic subjects, conversion into glucose of gluconeogenic precursors could represent 30% of splanchnic glucose output versus 20% in lean nondiabetic subjects (8). Although net splanchnic substrate uptake cannot account for the whole of GNG, this finding is nevertheless compatible with enhanced GNG in diabetes. Finally, tracer studies have shown that in obese type 2 diabetic patients...

Although hyperuricemia is a frequent finding in insulin-resistant states, insulin's effect on renal uric acid (UA) handling is not known. In 20 healthy volunteers, diastolic blood pressure, body weight, and fasting plasma insulin were positively (and age was negatively) related to fasting plasma UA concentrations, together accounting for 53% of their variability. During an insulin clamp, urine flow was lower than during fasting conditions (1.01 +/- 0.12 vs. 1.56 +/- 0.32 ml/min, P = 0.04), whereas creatinine clearance was unchanged (129 +/- 7 and 131 +/- 9 ml/min, P = not significant). Hyperinsulinemia did not alter serum UA concentrations (303 +/- 13 vs. 304 +/- 12 microM) but caused a significant decrease in urinary UA excretion [whether expressed as absolute excretion rate (1.66 +/- 0.21 vs. 2.12 +/- 0.23 mumol/min, P = 0.03), clearance rate (5.6 +/- 0.8 vs. 7.3 +/- 0.8 ml/min, P = 0.03), or fractional excretion (4.48 +/- 0.80 ml/min vs. 6.06 +/- 0.64%, P < 0.03)]. Hyperinsulinemia was also associated with a 30% (P < 0.001) fall in urine Na excretion. Fractional UA excretion was related to Na fractional excretion under basal conditions (r = 0.59, P < 0.01) and during the insulin period (r = 0.53, P < 0.02). Furthermore, the insulin-induced changes in fractional UA and Na excretion correlated with one another (r = 0.66, P < 0.001). Physiological hyperinsulinemia acutely reduces urinary UA and Na excretion in a coupled fashion.

RYGB and SLG have a similar impact on diabetes remission, of which baseline β-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.