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Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. Academic laboratory setting. An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients. • Duodenal-jejunal bypass liner (DJBL) induced food intake-independent weight loss • Bile acids and GLP-1 increased but not insulin sensitivity • Hypoglycemia counterregulation was impaired during duodenal exclusion • Removal of the DJBL improved measures of glucose homeostasis [ABSTRACT FROM AUTHOR]

Marking insulin's centennial, we share stories of researchers and clinicians whose seminal work has advanced our understanding of insulin, islet biology, insulin resistance, and diabetes. The past century of pursuing the "hormone of hormones" and advancing diabetes therapies is replete with stories of collaboration, perseverance, and triumph. [ABSTRACT FROM AUTHOR]

Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism ("glucose effectiveness"); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA. • Control of glucose production • Hepatic and extrahepatic Insulin clearance • Glucose effectiveness and hepatic glucose uptake • Ethnic differences in insulin clearance • Pathogenesis of Type 2 diabetes [ABSTRACT FROM AUTHOR]

Context Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. Study Subjects and Methods Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60 mU/m 2 /min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), β-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. Main Findings Incremental glucagon levels were ~ 3-fold higher during hypoglycemia ( P = 0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and β-hydroxybutyrate did not differ. At target glucose levels of ~ 52 mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~ 40% ( P = 0.02) in PCOS, compared to control women, despite ~ 20% higher steady-state insulin levels ( P = 0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~ 50% higher ( P = 0.02). PCOS status ( P = 0.04) and IMGD ( P = 0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. Principal Conclusions Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS. [ABSTRACT FROM AUTHOR]

For some time, it has been clear that elevated glucose is detrimental to the organism. A plethora of medicines have been introduced to reduce the fasting and postprandial glucose levels (including insulin, glucagon-like peptide receptor 1 [GLP-1] agonists, and sodium-glucose co-transporter 2 [SGLT2] inhibitors, among others). Although these medications are useful to reduce tissue exposure to glucose, no single compound and no combination have been able to totally normalize the blood sugar. Thus, it was astonishing when it was reported that surgery of the gastrointestinal tract could not only reduce obesity but also normalize the blood sugar. These discoveries have transformed diabetes research. What is it about bariatric surgery that causes the remarkable amelioration of glucose homeostasis dysregulation? The answer to this million dollar question is a billion dollar answer. However, a new perspective could shed some light and help provide a clear path for investigation. Instead of asking what does bariatric surgery do to change the pathophysiology, we can ask what pathophysiology and risk factors confer a greater success with remission and improved disease state after surgery. Work from our laboratory and others can help to offer a physiologic basis for which mechanisms may be put into play when the anatomy is altered during surgery. Here, we do not offer an explanation of the mechanism of action of bariatric surgery, but rather provide a background on the regulation of blood glucose and how it is altered during both the diseased state and, as available, the remission state. [ABSTRACT FROM AUTHOR]

Objective Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. Methods Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. Results Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic β-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (S I ). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus. Conclusions The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study. [ABSTRACT FROM AUTHOR]

Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake, but this is blocked in insulin resistance. As glucotoxicity is associated with endothelial dysfunction, the observed hyperglycemia in diet-induced obese dogs may inhibit insulin access to muscle cells, and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in modest hyperglycemia, similar to that induced by a high fat diet. Methods During normoglycemic (100 mg/dl) and moderately hyperglycemic (120 mg/dl) clamps in anesthetized canines, sequential doses of insulin were injected into the vastus medialis of one hindlimb; the contra-lateral limb served as a control. Plasma samples were collected and analyzed for insulin content. Lymph vessels of the hind leg were also catheterized, and lymph samples were analyzed as an indicator of interstitial insulin concentration. Results Insulin injection increased lymph insulin in normoglycemic animals, but not in hyperglycemic animals. Muscle glucose uptake was elevated in response to hyperglycemia, however the insulin-mediated glucose uptake in normoglycemic controls was not observed in hyperglycemia. Modest hyperglycemia prevented intra-muscularly injected insulin from diffusing through the interstitial space reduced insulin-mediated glucose uptake. Conclusion Hyperglycemia prevents the appearance of injected insulin in the interstitial space, thus reducing insulin action on skeletal muscle cells. [ABSTRACT FROM AUTHOR]

Background: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. Objective: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20% E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. Methods: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. Results: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference ±SE:0 .4 7 ± 0.14 mmol/L; P= 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (p = -0.18, P= 0.03) and positively correlated with changes in the acute insulin response to glucose (p = 0.15, P= 0.05). Conclusions: These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937. [ABSTRACT FROM AUTHOR]

Prevalence of Type 2 diabetes has increased at an alarming rate, highlighting the need to correctly predict the development of this disease in order to allow intervention and thus, slow progression of the disease and resulting metabolic derangement. There have been many recent 'advances' geared toward the detection of pre-diabetes, including genome wide association studies and metabolomics. Although these approaches generate a large amount of data with a single blood sample, studies have indicated limited success using genetic and metabolomics information alone for identification of disease risk. Clinical assessment of the disposition index (DI), based on the hyperbolic law of glucose tolerance, is a powerful predictor of Type 2 diabetes, but is not easily assessed in the clinical setting. Thus, it is evident that combining genetic or metabolomic approaches for a more simple assessment of DI may provide a useful tool to identify those at highest risk for Type 2 diabetes, allowing for intervention and prevention. [ABSTRACT FROM AUTHOR]

Abstract: Lipoprotein lipase (LPL), the enzyme responsible for hydrolyzing triglyceride (TG) in plasma lipoproteins, is a key regulator of plasma TG levels. In Caucasians, postheparin-LPL (PH-LPL) activity is impaired in the presence of insulin resistance and leads to elevated TG levels. However, African Americans are often both insulin-resistant and normotriglyceridemic. But in African Americans, the effect of insulin resistance on PH-LPL activity has not been studied. In African Americans, if insulin resistance is not associated with a decrease in PH-LPL activity, this could account for the simultaneous presence of insulin resistance and normotriglyceridemia. Therefore, our goal was to determine in African Americans the relationship between insulin resistance and PH-LPL activity. In a cross-sectional study of 107 nondiabetic African Americans (57 men and 50 women; age mean ± SD, 35 ± 8 years, range 22-50 years; body mass index 31.6 ± 7.9 kg/m2, range 18.5-54.7 kg/m2), fasting TG levels and PH-LPL activity were determined. Visceral adipose tissue was measured by abdominal computed tomographic scan. Insulin resistance was determined by the insulin sensitivity index (S I). Subjects were divided into tertiles by S I. The range of S I in each tertile was 12.75 to 3.99, 3.87 to 2.20, 2.06 to 0.17 mU · L−1 · min−1. Insulin resistance was defined as being in the third tertile. TG levels in the men and women were 82.2 ± 35.5 versus 56.4 ± 30.1 mg/dL, P < .001. There were no sex difference in PH-LPL activity (8.9 ± 2.5 vs 9.6 ± 3.2 mmol/h per liter, P = .30) or S I (3.65 ± 2.59 vs 3.23 ± 1.89 L · mU−1 · min−1, P = .49). Although 47% of the subjects were obese, only 4% of subjects had hypertriglyceridemia (TG ≥150 mg/dL). By 2 separate analyses, PH-LPL was a major determinant of TG levels. First, there was a significant inverse correlation between PH-LPL activity and TG levels (men: r = −0.46, P < .001; women: r = −0.28, P = .046). Second, in the multiple regression analysis with TG as the dependent variable and PH-LPL, age, sex, S I, and visceral adipose tissue as independent variables, adjusted R 2 was 54% and the effect of PH-LPL on TG levels was highly significant(P < .001). However, insulin resistance did not appear to influence PH-LPL activity. This is demonstrated in 3 ways: first, PH-LPL activity was not different in the S I tertiles (9.10 ± 2.75, 9.52 ± 2.91, 9.13 ± 2.89 mmol/h per liter, P = .78); the correlation between PH-LPL and S I was not significant (men: r = 0.09, P = .51; women: r = −0.03, P = .78), and a multiple regression with PH-LPL as the dependent variable and age, S I, body mass index, and sex as independent variables, adjusted R 2 was <2% and the contribution of S I was not significant (P = .53). Hence, in African Americans, increased PH-LPL activity is associated with a decrease in TG levels. The lack of an effect of insulin resistance on PH-LPL could allow LPL to clear TG even in the presence of insulin resistance and explain the coexistence of insulin resistance and normotriglyceridemia in African Americans. [Copyright &y& Elsevier]

PURPOSE: Insulin resistance and visceral adiposity are associated with increased risk of type 2 diabetes. In this report, we describe the methods of the IRAS Family Study, which was designed to identify the genetic and environmental risk factors for insulin resistance and visceral adiposity.METHODS: Families from two ethnic groups (African American and Hispanic) have been recruited from three clinical sites. Blood samples for DNA as well as other standard measures were collected. A CT scan (visceral adiposity) and a frequently sampled glucose tolerance test (insulin resistance) were performed. Preliminary estimates of heritability for indirect measures related to insulin resistance and visceral adiposity were obtained using a variance components approach in the first 93 families (approximately 1000 individuals).RESULTS: Estimates of heritability ranged from low (0.08) for fasting insulin and HOMA, to moderate (0.28) for fasting glucose, to high (0.54) for BMI. After adjustment for age, gender and ethnicity, all heritability estimates were significantly greater than zero (p < 0.05).CONCLUSIONS: These results are consistent with the expectation that intermediate measures of insulin resistance and visceral adiposity are heritable, and that the IRAS Family Study has statistical power to detect these intermediate phenotypes of type 2 diabetes and atherosclerosis. [Copyright &y& Elsevier]

Highlights • Hypothalamic preoptic area (POA) cooling induces thermogenic responses typically observed during cold exposure in rats. • Short-term POA cooling mimics aspects of the glucoregulatory response to cold exposure. • Long-term POA cooling improves glucose tolerance. Abstract Normal glucose homeostasis depends on the capacity of pancreatic β-cells to adjust insulin secretion in response to a change of tissue insulin sensitivity. In cold environments, for example, the dramatic increase of insulin sensitivity required to ensure a sufficient supply of glucose to thermogenic tissues is offset by a proportionate reduction of insulin secretion, such that overall glucose tolerance is preserved. That these cold-induced changes of insulin secretion and insulin sensitivity are dependent on sympathetic nervous system (SNS) outflow suggests a key role for thermoregulatory neurons in the hypothalamic preoptic area (POA) in this metabolic response. As these POA neurons are themselves sensitive to changes in local hypothalamic temperature, we hypothesized that direct cooling of the POA would elicit the same glucoregulatory responses that we observed during cold exposure. To test this hypothesis, we used a thermode to cool the POA area, and found that as predicted, short-term (8-h) intense POA cooling reduced glucose-stimulated insulin secretion (GSIS), yet glucose tolerance remained unchanged due to an increase of insulin sensitivity. Longer-term (24-h), more moderate POA cooling, however, failed to inhibit GSIS and improved glucose tolerance, an effect associated with hyperthermia and activation of the hypothalamic-pituitary-adrenal axis, indicative of a stress response. Taken together, these findings suggest that POA cooling is sufficient to recapitulate key glucoregulatory responses to cold exposure. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown. Methods: We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (SI) and (4) pancreatic function (“disposition index”, DI) by intravenous glucose tolerance test. Results: At baseline, groups (risperidone: n =28; olanzapine: n =31) were overweight or obese by body mass index (risperidone: 28.4±5.4, olanzapine: 30.6±7.0kg/m2). Both drugs induced weight gain (p <0.004). Total adiposity was increased by olanzapine at 6 weeks (p =0.0006) and by both treatments at 24 weeks (p <0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p <0.003). S I did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S I, we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p <0.02); no increase was observed with risperidone. There were modest downward trends for S I with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p =0.033), indicating inadequate pancreatic compensation for insulin resistance. Conclusions: This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications. [Copyright &y& Elsevier]