Salvatore Calanna

Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes: Systematic review and meta-analysis of clinical studies

OBJECTIVE To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests. RESEARCH DESIGN AND METHODS Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied. RESULTS Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n = 363) exhibited no significant differences (P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min−1), and time-corrected incremental area under the curve (iAUC × min−1) in comparison with nondiabetic control subjects (n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min−1 to be reduced and showed tAUC and tAUC × min−1 to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min−1), BMI (tAUC, iAUC, and iAUC × min−1), and HbA1c (iAUC and iAUC × min−1) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA1c on GIP responses and showed a positive influence of BMI on GIP responses. CONCLUSIONS Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA1c are associated with reduced GIP secretion.

Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m2, HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a “recovery phase.” During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg−1, P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.

Glucose-dependent insulinotropic polypeptide: blood glucose stabilizing effects in patients with type 2 diabetes.

CONTEXT Patients with type 2 diabetes mellitus (T2DM) have clinically relevant disturbances in the effects of the hormone glucose-dependent insulinotropic polypeptide (GIP). OBJECTIVE We aimed to evaluate the importance of the prevailing plasma glucose levels for the effect of GIP on responses of glucagon and insulin and glucose disposal in patients with T2DM. DESIGN AND SETTING We performed a single center, placebo-controlled, cross-over, experimental study. PATIENTS We studied twelve patients with T2DM (age: 62 ± 1 years [mean ± SEM], body mass index: 29 ± 1 kg/m(2); glycosylated hemoglobin A1c: 6.5 ± 0.1% [48 ± 2 mmol/mol]). INTERVENTION We infused physiological amounts of GIP (2 pmol × kg(-1) × min(-1)) or saline. MAIN OUTCOME MEASURES We measured plasma concentrations of glucagon, glucose, insulin, C-peptide, intact GIP, and amounts of glucose needed to maintain glucose clamps. RESULTS During fasting glycemia (plasma glucose ∼8 mmol/L), GIP elicited significant increments in both insulin and glucagon levels, resulting in neutral effects on plasma glucose. During insulin-induced hypoglycemia (plasma glucose ∼3 mmol/L), GIP elicited a minor early-phase insulin response and increased glucagon levels during the initial 30 minutes, resulting in less glucose needed to be infused to maintain the clamp (29 ± 8 vs 49 ± 12 mg × kg(-1), P < .03). During hyperglycemia (1.5 × fasting plasma glucose ∼12 mmol/L), GIP augmented insulin secretion throughout the clamp, with slightly less glucagon suppression compared with saline, resulting in more glucose needed to maintain the clamp during GIP infusions (265 ± 21 vs 213 ± 13 mg × kg(-1), P < .001). CONCLUSIONS In patients with T2DM, GIP counteracts insulin-induced hypoglycemia, most likely through a predominant glucagonotropic effect. In contrast, during hyperglycemia, GIP increases glucose disposal through a predominant effect on insulin release.

Cardiovascular Risk Profile in Subjects With Prediabetes and New-Onset Type 2 Diabetes Identified by HbA 1c According to American Diabetes Association Criteria

OBJECTIVE We investigated the cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria. RESEARCH DESIGN AND METHODS Arterial stiffness, intima-media thickness (IMT), soluble receptor for advanced glycation end products (sRAGEs), and oral glucose tolerance test (OGTT) were evaluated in 274 subjects without a previous history of diabetes. The subjects were stratified into three groups according to the HbA1c levels. RESULTS The subjects with prediabetes (n = 117, HbA1c 5.7–6.4% [39–46 mmol/mol]) showed a higher augmentation (Aug), augmentation index (AugI), and IMT compared with those with lower HbA1c; however, these values were similar to those of subjects with HbA1c >6.5% (48 mmol/mol). When we further analyzed the subjects with prediabetes but included only subjects with normal glucose tolerance (NT) in the analysis, AugI and IMT still remained significantly higher than their levels in control subjects with HbA1c <5.7% (39 mmol/mol). After multiple regression analyses including several cardiovascular risk factors, only HbA1c, age, and sRAGE were significantly correlated with the IMT, whereas age and 1-h postload glucose were the major determinants of AugI. CONCLUSIONS Our data show that subjects with prediabetes according to HbA1c, but with both NT according to the OGTT and normal fasting glycemia, have an altered IMT and AugI. These data suggest that a simple, reproducible, and less expensive marker such as HbA1c may be better able to identify prediabetic subjects at high cardiovascular risk compared with fasting glycemia or OGTT alone.

Beta and alpha cell function in metabolically healthy but obese subjects: Relationship with entero-insular axis†

Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero‐insular axis.

Chronic Exposure to GLP-1 Increases GLP-1 Synthesis and Release in a Pancreatic Alpha Cell Line (α-TC1): Evidence of a Direct Effect of GLP-1 on Pancreatic Alpha Cells

Aims/Hypothesis Incretin therapies, which are used to treat diabetic patients, cause a chronic supra-physiological increase in GLP-1 circulating levels. It is still unclear how the resulting high hormone concentrations may affect pancreatic alpha cells. The present study was designed to investigate the effects of chronic exposure to high GLP-1 levels on a cultured pancreatic alpha cell line. Methods α-TC1-6 cell line was cultured in the presence or absence of GLP-1 (100 nmol/l) for up to 72 h. In our model GLP-1 receptor (GLP-1R) was measured. After the cells were exposed to GLP-1 the levels of glucagon secretion were measured. Because GLP-1 acts on intracellular cAMP production, the function of GLP-1R was studied. We also investigated the effects of chronic GLP-1 exposure on the cAMP/MAPK pathway, Pax6 levels, the expression of prohormone convertases (PCs), glucagon gene (Gcg) and protein expression, glucagon and GLP-1 production. Results In our model, we were able to detect GLP-1R. After GLP-1 exposure we found a reduction in glucagon secretion. During further investigation of the function of GLP-1R, we found an activation of the cAMP/MAPK/Pax6 pathway and an increase of Gcg gene and protein expression. Furthermore we observed a significant increase in PC1/3 protein expression, GLP-1 intracellular content and GLP-1 secretion. Conclusions/Interpretation Our data indicate that the chronic exposure of pancreatic alpha cells to GLP-1 increases the ability of these cells to produce and release GLP-1. This phenomenon occurs through the stimulation of the transcription factor Pax6 and the increased expression of the protein convertase PC1/3.

Early phase insulin secretion is increased in subjects with normal fasting glucose and metabolic syndrome: a premature feature of beta-cell dysfunction

BACKGROUND AND AIMS Metabolic syndrome (MS) has been mainly related to insulin resistance, but the role of changes in insulin secretion has not been thoroughly investigated. METHODS AND RESULTS Using an oral glucose tolerance test (OGTT) we studied beta-cell function and insulin sensitivity in subjects with normal fasting glucose with and without MS, and their relationship to fatty liver which was evaluated by abdominal-ultrasonography. In MS early phase insulin secretion, as measured by insulinogenic index (IG(30)), was increased (p<0.05) independently from insulin sensitivity. Furthermore IG(30) was progressively higher as the number of factors needed for the diagnosis of MS increased (p<0.01). Insulin and C-peptide AUC were also increased (p<0.01 and p<0.05, respectively) but, in contrast to IG(30), these differences disappeared when ISI was used as a covariate. After OGTT, 51% of the subjects with MS had altered post-load glucose tolerance compared to 24.9% without MS (p<0.01). In both groups, the altered glucose tolerance was associated with a similar IG(30) reduction. In normo-tolerant subjects with MS the IG(30) was higher (+54.1%, p<0.01), and this elevation occurred irrespective of ISI; however, the beta-cell compensatory capacity for insulin resistance (disposition index) was impaired (p<0.001). Fatty liver was more frequent (p<0.001) and more severe (p<0.01) in MS, and it was significantly related to total AUC-insulin (p<0.001), independently from ISI. CONCLUSION These findings indicate that the prevalence of altered tolerance is more frequent in subjects with normal fasting glucose and MS. The hyperinsulinemia might not only be an adaptive response to insulin resistance, but a primary defect of beta-cell function contributing to glucose intolerance.

Separate impact of metabolic syndrome and altered glucose tolerance on early markers of vascular injuries

OBJECTIVE We investigated the separate impact of metabolic syndrome (MS) and altered glucose tolerance on early markers of vascular injuries. METHODS Intima-media thickness (IMT) and pulse wave analysis (PWA), were evaluated in 132 overweight or obese subjects, with (MS(+)) or without (MS(-)) MS; subjects were further classified as normotolerant (NT) or with altered glucose tolerance (AGT) according to a 2 h oral glucose tolerance test (OGTT). RESULTS In MS(+) patients, IMT was higher than in the MS(-) group, and PWA revealed higher augmentation pressure (Aug, the contribution that wave reflection makes to systolic arterial pressure) and lower subendocardial viability ratio (SEVR, an estimate of myocardial perfusion). When analyzed according to glucose tolerance, IMT was higher in MS(+)NT subjects and AGT patients with and without MS, vs. MS(-)NT subjects. Logistic regression modeling showed that both AGT and MS were independently associated with increased IMT. However, only MS remained associated with IMT after adjustment for age. SEVR was reduced only in MS(+) patients, independently of glucose tolerance. In both groups, Aug and AugI were higher in the AGT group, but the correlation with 2 h-plasma glucose disappeared when corrected for age. CONCLUSION Both MS and AGT altered IMT, but the effect of AGT disappears when age is added to the multiple regression model. In contrast, arterial stiffness was affected differently in the two categories: in subjects with MS, the subendocardial viability ratio (an estimate of myocardial perfusion) was impaired, while in subjects with AGT, both Aug and AugI were increased. These data suggest that applying the definition of MS might help to better characterize cardiovascular risk in subjects with altered glucose tolerance or obesity.

Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes

BACKGROUND AND AIMS We aimed to investigate lipid abnormalities and liver steatosis in patients with HbA1c-defined prediabetes and type 2 diabetes compared to individuals with HbA1c-defined normoglycaemia. METHODS AND RESULTS Ninety-one subjects with prediabetes according to HbA1c, i.e. from 5.7 to 6.4% (39-46 mmol/mol), 50 newly diagnosed patients with HbA1c-defined type 2 diabetes (HbA1c ≥6.5% [≥48 mmol/mol]), and 67 controls with HbA1c lower than 5.7% (<39 mmol/mol), were studied. Fasting blood samples for lipid profiles, fatty liver index (FLI), bioimpedance analysis, ultrasound scan of the liver, and BARD (body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes) score for evaluation of liver fibrosis, were performed in all subjects. In comparison to controls, subjects with prediabetes were characterised by: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure, triglycerides levels and apolipoprotein B/apolipoprotein AI ratio, higher FLI, increased prevalence of and more severe hepatic steatosis, similar BARD score, and higher total body fat mass. In comparison to subjects with diabetes, subjects with prediabetes exhibited: similar blood pressure and apolipoprotein B/apolipoprotein AI ratio, similar FLI, reduced prevalence of and less severe hepatic steatosis, lower BARD score, increased percent fat and lower total body muscle mass. In comparison to controls, subjects with diabetes showed: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure and triglycerides levels, higher FLI, increased prevalence of and more severe hepatic steatosis, higher BARD score, and higher total body muscle mass. Moreover, HbA1c was correlated with BMI, HOMA-IR, triglycerides, HDL cholesterol, AST, and ALT. CONCLUSIONS Subjects with HbA1c-defined prediabetes and type 2 diabetes, respectively, are characterised by abnormalities in lipid profile and liver steatosis, thus exhibiting a severe risk profile for cardiovascular and liver diseases.

The Role of Glucagon-like Receptor-1 Agonists in the Metabolic Syndrome

The incretin hormone, glucagon-like peptide-1 (GLP-1) is an intestinal hormone released in response to nutrients ingestion, from entero-endocrine L cells. GLP-1 enhances glucose-induced insulin secretion from the beginning of a meal (incretin effect), and, therefore, plays an essential role in the regulation of glucose homeostasis. Besides stimulating insulin release and thereby glucose-uptake, GLP-1 has several other actions. It inhibits glucagon secretion glucose-dependently, and exerts effects on lipid metabolism and blood pressure. Moreover, GLP-1 regulates body weight by inhibiting appetite and gastric emptying and, perhaps, stimulating resting energy expenditure. Because of these actions, GLP-1 was recently introduced to the market as a new therapy of type 2 diabetes.