Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

OBJECTIVETo identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study.RESEARCH DESIGN AND METHODSA total of 91 youth (10–19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA_1c increase ≥0.5% from baseline).RESULTSGlycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05–0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA_1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05).CONCLUSIONSGlycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.     

Natural History of Insulin Sensitivity and Insulin Secretion in the Progression From Normal Glucose Tolerance to Impaired Fasting Glycemia and Impaired Glucose Tolerance: The Inter99 Study

OBJECTIVE—The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined IFG/IGT.RESEARCH DESIGN AND METHODS—Baseline and 5-year follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT, or NGT at the 5-year follow-up were examined with an oral glucose tolerance test (n = 3,145). Insulin sensitivity index (ISI), homeostasis model assessment of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated.RESULTS—Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI, HOMA-IS, EPIR, and disposition index during the 5-year follow-up.CONCLUSIONS—A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack of β-cell compensation is associated with the development of i-IGT. Thereby, i-IFG and i-IGT appear to result from different underlying mechanisms, which may have implications for the prevention and treatment of the diabetes that succeeds them.During the past few years, it has been established that the pre-diabetic conditions of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined fasting and postchallenge hyperglycemia (IFG/IGT) represent distinct pathways to diabetes. These pre-diabetic states are characterized by different degrees of insulin sensitivity, insulin secretion, and hepatic glucose output as well as secretion of glucagon and incretin hormones (1–8). Nevertheless, the primary abnormalities inherent in the different pre-diabetic conditions are still unknown.Randomized trials have shown beneficial effects of lifestyle intervention on diabetes risk in individuals with i-IGT and IFG/IGT (9,10), but whether lifestyle interventions have the same preventive effects in individuals with i-IFG is not known. Indeed, a more profound insight into the pathogenesis of the disease is needed to optimize prevention and treatment of type 2 diabetes. In particular, focus on the initial defects responsible for hyperglycemia in the fasting and postprandial states is essential for interrupting the progression from normal to abnormal glucose metabolism.Most previous studies have examined the pathophysiology of pre-diabetes in cross-sectional settings without knowing the time of onset of glycemic abnormalities. However, the observed abnormalities in pre-diabetes may be related to traits already apparent in the normoglycemic state. Prospective studies are therefore needed to clarify whether this is the case or whether the metabolic abnormalities associated with i-IFG, i-IGT, and IFG/IGT develop simultaneously with the increases in fasting and/or postchallenge plasma glucose levels.The aim of this study was to describe the natural history of insulin sensitivity and insulin secretion during the progression from normal glucose tolerance (NGT) to the pre-diabetic states of i-IFG, i-IGT, and combined IFG/IGT.     

Corneal Confocal Microscopy Detects Neuropathy in Subjects With Impaired Glucose Tolerance

OBJECTIVE

Impaired glucose tolerance (IGT) represents one of the earliest stages of glucose dysregulation and is associated with macrovascular disease, retinopathy, and microalbuminuria, but whether IGT causes neuropathy is unclear.

RESEARCH DESIGN AND METHODS

Thirty-seven subjects with IGT and 20 age-matched control subjects underwent a comprehensive evaluation of neuropathy by assessing symptoms, neurological deficits, nerve conduction studies, quantitative sensory testing, heart rate variability deep breathing (HRVdb), skin biopsy, and corneal confocal microscopy (CCM).

RESULTS

Subjects with IGT had a significantly increased neuropathy symptom profile (P < 0.001), McGill pain index (P < 0.001), neuropathy disability score (P = 0.001), vibration perception threshold (P = 0.002), warm threshold (P = 0.006), and cool threshold (P = 0.03), with a reduction in intraepidermal nerve fiber density (P = 0.03), corneal nerve fiber density (P < 0.001), corneal nerve branch density (P = 0.002), and corneal nerve fiber length (P = 0.05). No significant difference was found in sensory and motor nerve amplitude and conduction velocity or HRVdb.

CONCLUSIONS

Subjects with IGT have evidence of neuropathy, particularly small-fiber damage, which can be detected using skin biopsy and CCM.     

Efficacy of Primary Prevention Interventions When Fasting and Postglucose Dysglycemia Coexist: Analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2)

OBJECTIVE

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have different pathophysiological abnormalities, and their combination may influence the effectiveness of the primary prevention tools. The hypothesis was tested in this analysis, which was done in a pooled sample of two Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2).

RESEARCH DESIGN AND METHODS

Researchers analyzed and followed up on the details of 845 of the 869 IGT subjects in the two studies for 3 years. Incidence of diabetes and reversal to normoglycemia (normal glucose tolerance [NGT]) were assessed in group 1 with baseline isolated IGT (iIGT) (n = 667) and in group 2 with IGT + IFG (n = 178). The proportion developing diabetes in the groups were analyzed in the control arm with standard advice (IDPP-1) (n = 125), lifestyle modification (LSM) (297 from both), metformin (n = 125, IDPP-1), and LSM + metformin (n = 121, IDPP-1) and LSM + pioglitazone (n = 298, IDPP-2). Cox regression analysis was used to assess the influence of IGT + IFG versus iIGT on the effectiveness of the interventions.

RESULTS

Group 2 had a higher proportion developing diabetes in 3 years (56.2 vs. 33.6% in group 1, P = 0.000) and a lower rate of reversal to NGT (18 vs. 32.1%, P = 0.000). Cox regression analysis showed that effectiveness of intervention was not different in the presence of fasting and postglucose glycemia after adjusting for confounding variables.

CONCLUSIONS

The effectiveness of primary prevention strategies appears to be similar in subjects with iIGT or with combined IGT + IFG. However, the possibility remains that a larger study might show that the effectiveness is lower in those with the combined abnormality.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have a high potential to convert to type 2 diabetes. While an elevated basal hepatic glucose output and impaired early phase insulin secretion are the major abnormalities in IFG, IGT is characterized by more severe muscle insulin resistance (IR) and defects in late insulin secretion (1). Among Asian Indians, higher degrees of IR and β-cell dysfunction are seen in IFG than in IGT (2).Analysis of six prospective studies among subjects with IGT showed that the incidence of diabetes varied widely from 23 to 62% within two to twenty-seven years of follow-up (3). The incidence was higher among populations with high prevalence of diabetes than in white populations. Incidence rates of diabetes in subjects with IFG or IGT or with a combined abnormality were varied in different populations (4–8).Primary prevention studies have been done among subjects with IGT in different ethnic populations (9–14). Among these, only the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial (12) recruited subjects with either isolated IFG (iIFG) or isolated IGT (iIGT) or both. Rosiglitazone was found to be a potent agent in preventing diabetes in this trial (12). The Diabetes Prevention Programme (DPP) (9) recruited subjects with a fasting glucose in the range of 5.3–6.9 mmol/l (95–125 mg/dl) and 2-h postglucose of 7.8–11 mmol/l (140–199 mg/dl) and nearly one-third of the participants had IFG by the present criteria (15).Results of the Indian Diabetes Prevention Programme-1 (IDPP-1) showed that a moderate lifestyle modification (LSM) or a small dose of metformin (500 mg/day) reduced the risk of diabetes in a relatively nonobese but insulin resistant Asian Indian population (13). In the IDPP-2 study, we noted that pioglitazone did not improve the efficacy of LSM in Asian Indians (14). In both studies, subjects with persistent IGT and fasting glucose levels below 6.9 mmol/l were recruited. Therefore, some participants also had IFG. In view of the higher degree of biochemical abnormalities occurring when fasting and postprandial dysglycemia coexisted, it was considered important to study whether the combined abnormalities influenced the cumulative incidence of diabetes in comparison with subjects with iIGT. To increase the sample size, data from both IDPP studies were pooled. The participants'' baseline characteristics were identical in the two studies.     

Corneal Confocal Microscopy Identifies Small-Fiber Neuropathy in Subjects With Impaired Glucose Tolerance Who Develop Type 2 Diabetes

OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.     

GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery

OBJECTIVE

Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP.

RESEARCH DESIGN AND METHODS

Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9–39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls.

RESULTS

Infusion of exendin-(9–39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9–39) 116.5 ± 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9–39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses.

CONCLUSIONS

The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.The beneficial effect of Roux-en-Y gastric bypass (RYGBP) surgery on glycemic control in morbidly obese subjects with type 2 diabetes mellitus (T2DM) is well established (1,2). However, the precise mechanisms mediating T2DM remission after RYGBP are not yet clear (3–5). Although it traditionally has been asserted that bariatric operations are associated with improvement of glucose tolerance merely by caloric restriction and weight loss, several lines of evidence support weight-independent mechanisms are involved (6–11). An enhanced postsurgical glucagon-like peptide-1 (GLP-1) secretion, inducing a normalized or exaggerated insulin secretion after meal intake, has been hypothesized to play a major role in the improved glucose tolerance after RYGBP (3). Association studies have demonstrated larger improvements of glucose tolerance early after RYGBP being associated with a larger GLP-1 response to nutrient intake as compared with other surgical or nonsurgical interventions resulting in equivalent weight loss (7–9). Likewise, an exaggerated GLP-1 response has been reported up to 10 years after RYGB in subjects with sustained T2DM remission, suggesting a key role of GLP-1 in maintaining normal glucose tolerance in the long term after this type of surgery (12). However, because association does not prove causation, these data do not definitely prove GLP-1 plays a critical role in T2DM remission after RYGBP.Understanding the role of endogenous GLP-1 in metabolic physiology has been greatly enhanced by the availability of a potent GLP-1 receptor antagonist, exendin-(9–39). Exendin-(9–39) blockade of GLP-1 action in healthy volunteers results in a significant enlargement of postprandial glucose excursions (13–17). Moreover, using hyperglycemic clamp technique in combination with a mixed meal test, Salehi et al. (18) demonstrated that blocking GLP-1 action results in a larger decrease in the insulin secretion rate in RYGBP-operated subjects (−33%) as compared with nonoperated controls (−16%). This study clearly supports GLP-1 as an important determinant of insulin secretion after RYGBP. However, the use of hyperglycemic clamp limited the ability of the study to investigate the relative importance of GLP-1 secretion on glucose tolerance. Furthermore, because only one-third of the study participants presented with T2DM before surgery, the study also was limited in establishing the role of GLP-1 secretion in the remission of T2DM. Of note, in Goto-Kakizaki rats (a nonobese rat model of T2DM) administration of exendin-(9–39) has been shown to totally reverse the improved glucose tolerance resulting from duodeno-jejunal exclusion surgery (an experimental metabolic surgery similar to RYGBP) (19).Against this background, the main aim of our study was to examine the effect of endogenous GLP-1 blockade by exendin-(9–39) on glucose tolerance in subjects who had undergone RYGBP and with T2DM antedating surgery that had remitted after the surgical procedure. As secondary aims, we evaluated the effect of exendin-(9–39) on the insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide (GIP) responses to meal intake. We evaluated individuals during the long-term after surgery to avoid the potential confounding effect of intense caloric restriction or rapid weight loss or both on glucose tolerance.     

Circulating Fibroblast Growth Factor-21 Is Elevated in Impaired Glucose Tolerance and Type 2 Diabetes and Correlates With Muscle and Hepatic Insulin Resistance

OBJECTIVE

Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

RESEARCH DESIGN AND METHODS

Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m² per min) combined with 3-[³H] glucose infusion.

RESULTS

Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).

CONCLUSIONS

Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.Fibroblast growth factors (FGFs) represent a group of peptides that regulate diverse biological functions, including cell differentiation, cell growth, and angiogenesis (1,2). Recently, a subfamily of FGFs that interact with nuclear receptors has been identified that plays an important role in liver, bone, and adipose tissue metabolism (3,4). This subfamily contains FGF-19, which regulates energy expenditure (5,6); FGF-23, which regulates phosphate metabolism and excretion (7); and the recently described FGF-21, which regulates glucose homeostasis (8,9).FGF-21 is a novel protein that has been implicated in the regulation of lipid and glucose metabolism under fasting and ketotic conditions (9,10). In murine models, FGF-21 was reported to be expressed predominantly in liver (11), but its expression has also been reported in adipose tissue and pancreatic β-cells (12). In a primate model of diabetes, Kharitonenkov et al. (9) reported a reduction in plasma glucose, insulin, triglycerides, LDL cholesterol, and HDL cholesterol levels following 6 weeks of recombinant FGF-21 administration. In diet-induced obese mice, FGF-21 reversed hepatic steatosis and improved insulin sensitivity (13). In adipose tissue, FGF-21 was shown to increase glucose uptake (9). Based on these observations, FGF-21 has been proposed as a potential therapeutic agent for type 2 diabetes in humans (14). However, few studies in humans have examined the relationship between FGF-21 and glucose/lipid metabolism. Chen et al. (15) reported that patients with newly diagnosed type 2 diabetes had significantly higher plasma FGF-21 concentrations than nondiabetic control subjects, and FGF-21 negatively correlated with fasting plasma glucose. More recently, Zhang et al. (16) found that FGF-21 concentrations are elevated in obese nondiabetic individuals compared with lean healthy control subjects and that the circulating levels correlated positively with adiposity and fasting insulin and negatively with HDL cholesterol. Conversely, in patients with anorexia nervosa, plasma FGF-21 concentrations are decreased and increased following weight gain (17). In the present study, we examined the relationship between plasma FGF-21 concentrations and direct measurements of peripheral and hepatic insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.     

Effect of Renin-Angiotensin System Blockade on Insulin Resistance and Inflammatory Parameters in Patients With Impaired Glucose Tolerance

OBJECTIVE

The study investigated the effect of angiotensin receptor blockers (ARB) on glucose homeostasis and inflammatory parameters in patients with impaired glucose tolerance (IGT).

RESEARCH DESIGN AND METHODS

We prospectively studied the insulin sensitivity index (ISI) and homeostasis model assessment–insulin resistance (HOMA-IR) in 13 obese males with IGT and in 13 matched control subjects with normal glucose tolerance (NGT) during hyperglycemic testing over 90 min. Adiponectin, retinol-binding protein 4 (RBP4), and high-sensitive C-reactive protein (hsCRP) were analyzed. Measurements were performed at baseline and after a 4-week treatment with 160 mg/day valsartan. The results of the IGT and NGT groups were compared.

RESULTS

At baseline, HOMA-IR (IGT 4.1 ± 3 vs. NGT 2.3 ± 1.0, P < 0.01), hsCRP (IGT 3.9 ± 1.9 vs. NGT 1.8 ± 1 mg/l, P < 0.05), and RBP4 (IGT 27.1 ± 2.1 vs. NGT 24.0 ± 2.0 ng/ml, P < 0.05) were significantly higher, whereas ISI (IGT 1.5 ± 0.9 vs. NGT 1.8 ± 1.2, P < 0.05) and plasma adiponectin (IGT 3.2 ± 0.9, NGT 5.2 ± 2.4 μg/ml, P < 0.05) were significantly lower in the IGT group compared with the NGT group. Under ARB, there was an increase in both groups of adiponectin (IGT 4.1 ± 1.9 μg/ml, NGT 6.3 ± 2.9 μg/ml, P < 0.05) and an increase in ISI (IGT 1.5 ± 0.9 to 2.3 ± 1 μg/ml, NGT 1.8 ± 1 to 2.5 ± 2 μg/ml, P < 0.05). HOMA-IR (4.1 ± 3 to 2.6 ± 2; P < 0.01), hsCRP (3.9 ± 1.9 to 1.8 ± 1 mg/l, P < 0.05), and RBP4 (27.1 ± 2.1 to 22.1 ± 1.8 ng/ml, P < 0.01) decreased significantly in the IGT group.

CONCLUSIONS

Insulin sensitivity and associated inflammatory factors improve under ARB in IGT patients.Insulin resistance has a causal role in type 2 diabetes, a crucial risk factor for cardiovascular and renal disease (1). Impaired glucose tolerance (IGT) represents an intermediate state of abnormal glucose regulation between normal glucose homeostasis and manifest diabetes. IGT is defined as elevated 2-h plasma glucose concentration >140 and <200 mg/dl after a 75-g oral glucose load in an oral glucose tolerance test (2). A combination of β-cell dysfunction and insulin resistance with decreased insulin sensitivity or responsiveness to the metabolic action of insulin plays a pathogenetic role. Insulin resistance is common in subjects with visceral adiposity, hypertension, hyperglycemia, and dyslipidemia. Patients with metabolic syndrome have a high risk of developing frank diabetes (3).Adiponectin is a fat-derived hormone specifically produced and secreted by adipocytes. This adipocytokine is considered an important modulator of insulin sensitivity in patients with IGT (4,5). Adiponectin levels decrease in the obese, which may be a contributing factor to insulin resistance. Anti-inflammatory properties also have been attributed to adiponectin. This is indicated by serum concentrations of adiponectin, which are inversely associated with inflammatory markers such as C-reactive protein (CRP). Retinol-binding protein 4 (RBP4) is another adipocyte-secreted molecule and is elevated in serum before development of overt diabetes (6).The interaction of these different metabolic and inflammatory parameters in IGT has not been fully clarified. Our study investigates insulin sensitivity and associated risk factors focusing on obese subjects with IGT. We tested the effect of a short-term 4-week angiotensin receptor blocker (ARB) treatment on glucose disposal and inflammatory markers in subjects with IGT.     

The Effect of DPT-1 Intravenous Insulin Infusion and Daily Subcutaneous Insulin on Endogenous Insulin Secretion and Postprandial Glucose Tolerance

OBJECTIVETo investigate the effect of parenteral insulin therapy on endogenous insulin secretion in the Diabetes Prevention Trial–Type 1 (DPT-1).RESULTSIV-I suppressed fasting and OGTT-stimulated C-peptide (62% and 40%, respectively), and it significantly lowered fasting glucose (67.4 ± 4.5 mg/dL during IV-I vs. 90.9 ± 1.8 mg/dL off insulin; P < 0.05). By contrast, post-OGTT glucose levels were significantly higher during IV-I: Glucose during IV-I versus off insulin at 120 min was 203.9 ± 15.1 vs. 151.6 ± 10.2 mg/dL, respectively (P < 0.05); 49% of OGTTs became transiently diabetic (>200 mg/dL at 120 min) when receiving IV-I. Fasting glucose was significantly lower when receiving SC-I versus when off insulin (85 ± 3 vs. 94 ± 2 mg/dL, respectively; P < 0.05), but SC-I did not significantly alter fasting or OGTT-stimulated C-peptide compared with being off insulin.CONCLUSIONSThese data demonstrate that the IV-I used in the DPT-1 markedly suppressed endogenous insulin secretion, which was frequently associated with postprandial glucose intolerance. SC-I, however, did not.     

Effects of Intravenous Glucose Load on Insulin Secretion in Patients With Ketosis-Prone Diabetes During Near-Normoglycemia Remission

OBJECTIVE

Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.

RESEARCH DESIGN AND METHODS

Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m²/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.

RESULTS

The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.

CONCLUSIONS

Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.The majority of obese African American patients with newly diagnosed diabetes presenting with unprovoked diabetic ketoacidosis (DKA) display clinical and metabolic features of type 2 diabetes during follow-up and are able to maintain near-normoglycemic remission from several months to years without insulin or oral agents (1–7). This variant of type 2 diabetes has been referred to in the literature as atypical diabetes, type 1B diabetes, and ketosis-prone type 2 diabetes (KPD) (1,6). We and others have reported that for more than half of the patients with KPD, aggressive insulin therapy for ∼10 weeks results in significant recovery of β-cell function and in improvement in insulin sensitivity to allow discontinuation of insulin therapy (2,3,5,8–10).The underlying mechanism for the transient insulin deficiency leading to severe hyperglycemia ketoacidosis in African Americans with KPD is unknown. It is possible that sustained hyperglycemia per se before the development of DKA downregulates the β-cell insulin production capacity. The concept of “glucotoxicity” has been put forward to explain the contribution of toxic effects of hyperglycemia on β-cell function (11). The ability of patients with KPD to be withdrawn from insulin therapy and remain in near-normoglycemic remission suggests hyperglycemia-induced transient β-cell dysfunction. However, it is not known exactly how the β-cells respond to hyperglycemia and whether patients with KPD during the near-normoglycemia remission phase will display deterioration of insulin secretion after a sustained glucose challenge. In this study, we hypothesized that, compared with obese type 2 diabetic patients with hyperglycemia and obese nondiabetic control subjects, obese African Americans with KPD during near-normoglycemia remission will experience a diminished insulin response to sustained elevations in blood glucose or β-cell glucotoxicity. All subjects underwent a 20-h infusion of dextrose solution with serial measurements of insulin, C-peptide, and blood glucose and a sequential arginine stimulation test before and after dextrose infusion.     

Iron Excess, Early Glucose Intolerance and Impaired Insulin Secretion in Idiopathic Haemochromatosis

Abstract. The relationship between iron storage and glucose metabolism was studied in 21 relatives of 4 patients with idiopathic haemochromatosis and in 10 healthy control subjects. In all individuals, plasma iron and iron binding capacity were measured and liver function was assessed. In addition, intravenous and oral glucose tolerance tests (IVGTT, OGTT), as well as tolbutamide (TTT) and insulin tolerance tests (ITT), were performed. Serum insulin (IRI) was measured. Liver biopsies were performed on the 21 relatives only.
In the relatives of patients with haemochromatosis, glucose tolerance was impaired and insulin secretion in response to hyperglycaemia diminished and/or delayed. Glucose intolerance increased with age but did not depend on abnormal liver function or excessive iron storage. Insulin release in response to tolbutamide was normal and insulin tolerance test failed to reveal insulin resistance.
The results suggest that:
1. There is an early glucose intolerance in healthy relatives of patients suffering from idiopathic haemochromatosis.
2. The glucose intolerance seems unrelated to measurable anomalies in iron metabolism.
3. The delayed insulin secretion in response to glucose resembles that observed in common maturity-onset diabetes mellitus.
4. The results obtained are compatible with the hypothesis that haemochromatosis and diabetes mellitus might be two distinct but genetically linked entities.     

Safety and Glycemic Outcomes With a Tubeless Automated Insulin Delivery System in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Clinical Trial

OBJECTIVEVery young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population.RESEARCH DESIGN AND METHODSA total of 80 children aged 2.0–5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy.RESULTSThere were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA_1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70–180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204).CONCLUSIONSUse of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.     

冠心病合并糖耐量受损患者糖化血红蛋白水平与冠脉病变的相关性研究

目的 探讨冠心病合并糖耐量受损患者糖化血红蛋白水平（HbA1c）与冠脉病变的相关性.方法 213例经冠脉造影确诊冠心病患者,根据口服75 g葡萄糖耐量试验结果,分为糖耐量正常的单纯冠心病组（NGT组）110例;冠心病合并糖耐量受损组（IGT组）103例.冠状动脉造影结果采用Gensini评分.结果 IGT组HbA1c水平、Gensini积分明显高于NGT组（P＜0.05）;IGT组重度狭窄（76-100%）及多支病变高于NGT组（P＜0.05）.Spearman等级相关分析提示,体重指数、餐后2 h血糖、甘油三酯、低密度脂蛋白胆固醇、高敏C反应蛋白、HbA1c与Gensini积分正相关.以Gensini积分为因变量进行多元回归分析,结果显示：HbA1c对冠脉狭窄程度有独立的预测价值.结论 冠心病合并糖耐量受损患者HbA1c与冠脉狭窄程度呈正相关,而且可作为其独立预测指标.     

Obstructive Sleep Apnea,Glucose Tolerance,and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

OBJECTIVEObstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes.RESEARCH DESIGN AND METHODSTwo hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m²) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA_1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models.RESULTSMean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA_1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-cell responses.CONCLUSIONSIn this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA_1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.     

The Coventry Diabetes Study: Prevalence of Diabetes and Impaired Glucose Tolerance in Europids and Asians

The Coventry Diabetes Study compared the prevalence of diabetesand impaired glucose tolerance in adult Asians and Europidsin relation to age, sex and body mass index. The study involveda cross-sectional house to house screening for diabetes in theelectoral ward of Foleshill, Coventry, a traditional area formigration into the city. Subjects with a high blood glucoseand 10 per cent of others were referred for a 75 g oral glucosetolerance test. Of the 10 304 adult residents aged 20 years or above, 3529 (64per cent) of 5508 Europids and 3692 (84 per cent) of 4395 Asianswere either screened for diabetes or already diabetic and 719(65 per cent of 1114 Europids and 780 (72 per cent) of 1084Asians invited to glucose tolerance test attended. Althoughthe prevalence of insulin-dependent diabetes was similar, theage adjusted prevalence of non-insulin-dependent diabetes was3.2 per cent (95 per cent confidence interval (CI): 2.6–4.0)and 4.7 per cent (CI per cent 4.0–5.5) in Europid malesand females but 12.4 per cent (CI 11.0–13.8) and 11.2CI per cent (10.0–12.5) in Asian males and females givingprevalence ratios of 3.9 per cent (3.1–5.0) in males and2.4 per cent (2.0–2.9) in females. These differences werenot due to differences in body mass index. The prevalence ofimpaired glucose tolerance was also higher in Asians aged below60 years, and in 65 per cent of Europids and 40 per cent ofasians non insulin-dependent diabetes was previously undiagnosed.The non-insulin-dependent diabetes/impaired glucose toleranceration was significantly higher in Asians than Europids. Non-insulin-dependent diabetes in Asinans differs from thatin Europids. Besides the higher overall prevalence, there isa greater proportion of males, a lower proportion of undiagnoseddisease, a younger age at diagnosis and a greater proportionof abnormal glucose tolerance that is due to non-insulin dependentdiabetes.     

Sleep Duration, Lifestyle Intervention, and Incidence of Type 2 Diabetes in Impaired Glucose Tolerance: The Finnish Diabetes Prevention Study

OBJECTIVE

Both short and long sleep duration have frequently been found to be associated with an increased risk for diabetes. The aim of the present exploratory analysis was to examine the association between sleep duration and type 2 diabetes after lifestyle intervention in overweight individuals with impaired glucose tolerance in a 7-year prospective follow-up.

RESEARCH DESIGN AND METHODS

A total of 522 individuals (aged 40–64 years) were randomly allocated either to an intensive diet-exercise counseling group or to a control group. Diabetes incidence during follow-up was calculated according to sleep duration at baseline. Sleep duration was obtained for a 24-h period. Physical activity, dietary intakes, body weight, and immune mediators (C-reactive protein and interleukin-6) were measured.

RESULTS

Interaction between sleep duration and treatment group was statistically significant (P = 0.003). In the control group, the adjusted hazard ratios (HRs) (95% CI) for diabetes were 2.29 (1.38–3.80) and 2.74 (1.67–4.50) in the sleep duration groups 9–9.5 h and ≥10 h, respectively, compared with for that of the 7–8.5 h group. In contrast, sleep duration did not influence the incidence of diabetes in the intervention group; for sleep duration groups 9–9.5 h and ≥10 h, the adjusted HRs (95% CI) were 1.10 (0.60–2.01) and 0.73 (0.34–1.56), respectively, compared with that in the reference group (7–8.5 h sleep). Lifestyle intervention resulted in similar improvement in body weight, insulin sensitivity, and immune mediator levels regardless of sleep duration.

CONCLUSIONS

Long sleep duration is associated with increased type 2 diabetes risk. Lifestyle intervention with the aim of weight reduction, healthy diet, and increased physical activity may ameliorate some of this excess risk.It has become increasingly evident that abnormal sleep patterns, such as short and long sleep durations, are associated with increased morbidity and mortality (1). The relationship between increased risk for type 2 diabetes and either short or long sleep has frequently been demonstrated in both men and women (2–4). The underlying mechanisms are still largely unknown. In an experimental study, sleep deprivation has been shown to have harmful effects on metabolic and endocrine functions (5). However, there are no plausible physiological or psychosocial explanations for the association between long sleep and diabetes. In fact, some studies have observed a stronger association between habitual long sleep and diabetes than that for short sleep (2,3). There is no evidence or consensus whether the relationship between long sleep and diabetes is causal or simply reflects confounding by other underlying factors that affect sleeping habits. However, there is growing evidence that many of the hypothesized factors for long sleep are strongly associated with obesity and metabolic syndrome (6,7). The objective of the present exploratory analysis was to examine the effect of lifestyle intervention on the association between sleep duration and type 2 diabetes in individuals with impaired glucose tolerance (IGT) in the Finnish Diabetes Prevention Study (DPS) (8,9).     

Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

OBJECTIVE

To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.

RESEARCH DESIGN AND METHODS

Subjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.

RESULTS

At baseline, type 2 diabetic subjects had elevated T_mG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the T_mG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.

CONCLUSIONS

The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the T_mG and threshold at which glucose is excreted in the urine.The current study was undertaken to examine the mechanism (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold) through which sodium-glucose transporter 2 (SGLT2) inhibition induces glucosuria in diabetic and nondiabetic subjects. In humans, the kidney filters ∼162 g of glucose per day (glomerular filtration rate [GFR] = 180 L/day × fasting plasma glucose [FPG] = ∼5 mmol/L [90 mg/dL]), and virtually all the filtered glucose is reabsorbed (1). The high-capacity, low-affinity SGLT2 in the proximal tubule reabsorbs ∼80–90% of filtered glucose (2,3). T_mG varies among individuals and averages ∼375 mg/min (2–4). Because the filtered glucose load does not exceed T_mG in nondiabetic individuals, all filtered glucose is reabsorbed and returned to the circulation. If the filtered glucose load exceeds the T_mG, all glucose in excess of the T_mG is excreted. The plasma glucose concentration at which the filtered glucose load reaches 375 mg/min is ∼10 mmol/L (180 mg/dL) (2–4). Above the T_mG, the glucose excretion rate increases linearly and parallels the increase in filtered glucose load. Glucose reabsorption and excretion curves display a nonlinear transition as T_mG is approached. This rounding of the curves is termed splay (Fig. 1). The plasma glucose concentration at which glucose first appears in the urine is termed threshold and corresponds to the beginning of the splay.Open in a separate windowFigure 1Relationship between the rate of urinary glucose reabsorption/renal glucose filtration and the plasma glucose concentration during SHC in type 2 diabetic and healthy subjects at baseline and after 7 days of dapagliflozin treatment. Thin line, rate of glucose filtration; ○, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of T_mG.In patients with poorly controlled type 1 or 2 diabetes, T_mG is increased (5,6). Similar observations have been made in diabetic animal models (7,8). At the molecular level, increased T_mG may be explained by increased SGLT2 mRNA and protein in the proximal tubule (9–11).SGLT2 inhibitors have been developed for the treatment of type 2 diabetes (4,12–14) and have proven to be efficacious in reducing glycated hemoglobin (HbA_1c) (12–16). Because their mechanism of action is independent of severity of insulin resistance and β-cell failure, they can be used at any stage of type 2 diabetes (14,16,17). Clinical trials with SGLT2 inhibitors have demonstrated that treatment in healthy subjects results in continuously excreted glucose in the absence of hyperglycemia (18,19), suggesting that factors other than a reduction in T_mG must account for the drug’s glucosuric effect. Because no previous study to our knowledge has comprehensively characterized the changes in renal glucose handling through which SGLT2 inhibitors augment renal glucose excretion in humans, the current study was undertaken to examine the mechanisms through which dapagliflozin produces its glucosuric effect in individuals with type 2 diabetes and those with normal glucose tolerance.     

No Difference in Small or Large Nerve Fiber Function Between Individuals With Normal Glucose Tolerance and Impaired Glucose Tolerance

OBJECTIVE

To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS

Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

RESULTS

There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

CONCLUSIONS

Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.A high prevalence of impaired glucose tolerance (IGT) in individuals with idiopathic neuropathy has been reported (1), but whether neuropathy already exists in the prediabetic stage, i.e., IGT, is unknown (2,3). In a population-based study, neuropathy was marginally more common in IGT than in normoglycemic controls (4), but others reported no difference in measures of neuropathy between IGT and normal glucose tolerance (NGT) (5,6).When addressing the question of whether “IGT neuropathy” truly exists, objective measures of nerve dysfunction are frequently crude and focused on large nerve fibers, and small nerve fiber dysfunction is often overlooked (1,4,6).Thus, our aim was to study measures of both small and large nerve function in well-characterized normoglycemic, IGT, and type 2 diabetic (T2D) individuals.     

2型糖尿病家系非糖尿病一级亲属第一时相胰岛素的变化

目的：探讨2型糖尿病家系非糖尿病一级亲属在糖耐量正常时胰岛素第一时相分泌情况。方法：收集江苏省常州市2型糖尿病家系中非糖尿病一级亲属（NGT组）42例、家系2型糖尿病（T2DM组）49例、并以无糖尿病家族史的46例健康成人为对照（NC组）。进行25g静脉葡萄糖耐量试验（IVGTT）测定空腹及IVGT后1、2、4、6、10min的血胰岛素水平。结果：2型糖尿病家系非糖尿病一级亲属0、1、4、6、10min胰岛素和健康成人对照组之间有统计学差异（P〈0．05）。结论：2型糖尿病家系中糖耐量正常的一级亲属胰岛素的第一时相分泌和没有遗传背景的健康成人已存在显著差异。