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Whether individuals with insulin resistance (IR) but without criteria for diabetes exhibit reduced mitochondrial oxidative capacity is unclear; addressing this question could guide research for new therapeutics. We investigated 248 participants without diabetes from the Baltimore Longitudinal Study of Aging (BLSA) to determine whether impaired mitochondrial capacity is associated with prediabetes, IR, and duration and severity of hyperglycemia exposure. Mitochondrial capacity was assessed as the postexercise phosphocreatine recovery time constant (τPCr) by 31P-magnetic resonance spectroscopy, with higher τPCr values reflecting reduced capacity. Prediabetes was defined using the American Diabetes Association criteria from fasting and 2-h glucose measurements. IR and sensitivity were calculated using HOMA-IR and Matsuda indices. The duration and severity of hyperglycemia exposure were estimated as the number of years from prediabetes onset and the average oral glucose tolerance test (OGTT) 2-h glucose measurement over previous BLSA visits. Covariates included age, sex, body composition, physical activity, and other confounders. Higher likelihood of prediabetes, higher HOMA-IR, and lower Matsuda index were associated with longer τPCr. Among 205 participants with previous OGTT data, greater severity and longer duration of hyperglycemia were independently associated with longer τPC In conclusion, in individuals without diabetes a more impaired mitochondrial capacity is associated with greater IR and a higher likelihood of prediabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CBIR) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CBIRs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action. RESEARCH DESIGN AND METHODS--We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KC1. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R-/-) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. RESULTS--ECs are generated within β-cells, which also express CBIRs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CBIR results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CBIR antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CBIR activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gαi-dependent manner. CONCLUSIONS--These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes. [ABSTRACT FROM AUTHOR]

Objective: Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.Research Design and Methods: Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.Results: Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse alpha-cells. In alphaTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion. CONCLUSIONS; GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting \(\beta\)-cells in the islets of Langerhans. Insulin itself positively regulates \(\beta\)-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate \(\beta\)-cell proliferation and if they influence insulin action. Research Design and Methods: We measured EC production in isolated human and mouse islets and \(\beta\)-cell line in response to glucose and KCl. We evaluated human and mouse islets, several \(\beta\)-cell lines, and CB1R-null (CB1R\(^{−/−}\)) mice for the presence of a fully functioning EC system. We investigated if ECs influence \(\beta\)-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. Results: ECs are generated within \(\beta\)-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in \(\beta\)-cells and leads to increased \(\beta\)-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased \(\beta\)-cell proliferation and mass, coupled with enhanced IR signaling in \(\beta\)-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on \(\beta\)-cells in a G\(\alpha_i\)-dependent manner. Conclusions: These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of \(\beta\)-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance \(\beta\)-cell function and proliferation in diabetes.

Approximately 1.25 million Americans have type 1 diabetes mellitus (T1DM), resulting from β-cell destruction. There is no known way to prevent it or to stop destruction of any remaining β-cells. Although the cannabinoid system, specifically cannabinoid 1 receptor (CB1R), is implicated in obesity and T2DM, its role, if any, in T1DM has not been studied. To address this, we induced β-cell destruction in wild type mice (WT: n=8) and mice in which CB1R was genetically nullified in β-cells only (β-CB1R-/-: n=8) in adulthood by five injections of streptozotocin (50 mg/kg intraperitoneally [IP]), a toxin selective for β-cells. We found that β-CB1R-/- mice had random blood glucose (BG) levels in the range of 137-289 mg/dL throughout the study period (28 days) as well as preserved insulin secretion with superior glucose tolerance after IP glucose (2g/kg) at day 8, 15 or 27, relative to their (random BG 500-600 mg/dL) WT littermates. CB1R knockout drove significant increases in pancreatic islet autophagic activity based on increased accumulation of autophagosome hallmarks (LC3B, Beclin-1, ATG5 and ATG7) and reduced p62 expression. Insulin and LC3B were colocalized in CB1R-deficient β-cells. Remarkably, the islets did not show the upregulation of ER unfolded protein response, which was present in β-cells of WT mice, while exerting the induction of protective chaperones. These anti-stress functions were accompanied by increased phosphorylation of AKT (ser) 473 and ERK in β-cells, which reveals a previously unrecognized route for PI3K-AKT pathway to activate the anti-apoptotic NFkB/p65 signaling that coordinately is permissive to β-cell survival. We conclude that CB1R nullification restores autophagy machinery as a novel signaling pathway to counteract ER stress-mediated cell death and confers resistance to β-cell destruction. We propose that CB1R is a potential therapeutic target during the honeymoon phase of T1DM. Disclosure: K. Aseer: None. J.M. Egan: None. [ABSTRACT FROM AUTHOR]

Cannabinoid 1 receptors (CB1Rs) are G protein-coupled receptors that are present in peripheral organs such as liver, pancreas, adipose tissue and skeletal muscle where they are involved in fine-tuning many metabolic functions. It was previously reported that liver-specific genetic deletion of CB1R (hCNR1-/-) mice fed high fat diets (HFD) had similar body weight to HFD-fed hCNR1+/+ mice, but they retained insulin sensitivity comparable to normal chow-fed (NCD) hCNR1+/+ mice. Therefore, this study was undertaken to uncover how hCB1Rs impact the insulin signaling pathway. Male hCNR1-/- and hCNR1+/+ mice were fed with a high fat high sugar diet (HFSD: N = 8-12) for 15 weeks. In contrast with the previous study of HFD only, HFSD-fed hCNR1-/- mice had less body weight gain than HFSD-fed hCNR1+/+ mice (25.1±2.7 vs. 19.8±1.7g), less fat accumulation in the liver, 1.3-fold increase in glucose disposal and 1.7-fold increase in insulin sensitivity compared to HFSD-fed hCNR1+/+ mice. Further study demonstrated that the lack of hepatic CB1R resulted in upregulated phosphorylation in liver of protein kinase B (AKT), causing activation of downstream target molecules, such as proline-rich AKT substrate 40 (PRAS40) in the mammalian target of rapamycin complex 1 (mTORC1). Similarly, primary hepatocytes isolated from hCNR1-/- mice had increased amounts of phosphorylated AKT and PRAS40 in comparison to hepatocytes from hCNR1+/+ mice. The co-immunoprecipitation studies clearly revealed hepatic CB1R modulates insulin signaling by the association or dissociation of the components of mTORC1. In support of these data, the deficiency of hepatic CB1R leads to upregulation of phosphoinositide 3-kinase (PI3K) class IB, p110γ, resulting in increased association between p110γ and G-protein beta. These findings indicate that genetic deletion of hepatic CB1R contributes to improved glucose homeostasis. Therefore, modulation of CB1R activity in liver may be a useful therapeutic in obese and diabetic individuals. Disclosure: Y. Kim: None. J.M. Egan: None. [ABSTRACT FROM AUTHOR]

Deals with a study which determined whether the effects of glucagon-like peptide-1 on glucose-induced insulin release are preserved in elderly patients with diabetes. Subjects; Procedures of the study; Significance.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from the enteroendocrine K-cells in response to food. Unlike the other incretin, glucagon-like peptide-1 (GLP-1), GIP is reported to have lost its insulinotropic effect and not have glucose-lowering properties in patients with type 2 diabetes mellitus (T2DM). We attempted to gain insight into the pathophysiology underlying the seeming lack of effects of GIP on glucose homeostasis in T2DM. We therefore administered synthetic human GIP (with a meal) to subjects who had T2DM, and then, for 6hr, took frequent blood samples to measure various factors known to be involved in glucose homeostasis. 22 insulin-naive subjects with T2DM (ages 52.6±9.3years; BMI 36.7±7.3kg/m²; HbA[sub 1c] 7.4±1.5%; fasting plasma glucose 155±46mg/dl; diabetes duration 4.3±4.2years; f/m ratio 13/9) that had been treated with diet alone, metformin and/or sulfonylurea were recruited. They stopped oral hypoglycemic medications for 5 days prior to testing and fasted for 8hr prior to 2 study visits, each visit separated by not less than 6 weeks. After 3 baseline blood draws, the subjects received continuous intravenous administration of either placebo (0.9%NaCl) or GIP (20ng/kg/min) for 180min starting with the first bite of a 550calorie mixed-meal, and 1g of acetaminophen to study gastric emptying. Frequent blood sampling took place over the subsequent 6hr (every 5min for the first 75min then every 15min until 180min and every 20min until 360min). Compared to placebo, GIP induced an increase in plasma insulin from 5-30min but a transient decrease in plasma glucose at the 10min time-point only (p<0.05). Intriguingly, and hitherto undescribed, GIP induced a later augmentation in glucagon secretion with a peak level at approximately 30min (p<0.05), a significant elevation in plasma glucose from 120-220min (p<0.05) and a decrease in GLP-I secretion at 135min that lasted for the remainder of the 6hr study period (p<0.05). Based on plasma acetaminophen levels, GIP did not affect gastric emptying and NEFAs were similar during both studies. In T2DM therefore, GIP, given at a pharmacological dose with a meal, still has an early, short-lived insulinotropic effect, resulting in a transient, clinically irrelevant plasma glucose drop. However, this was subsequently followed by increased plasma glucagon levels and worsening hyperglycemia. These findings make it unlikely that GIP or GIP receptor agonists will ever be useful as glucose-lowering agents. [ABSTRACT FROM AUTHOR]

Objective: Glycated hemoglobin (HbA₁(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels., Research Design and Methods: We studied associations with HbA₁(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA₁(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening., Results: Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c)., Conclusions: GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).