Racial/Ethnic Differences in Dementia Risk Among Older Type 2 Diabetic Patients: The Diabetes and Aging Study

OBJECTIVE

Although patients with type 2 diabetes have double the risk of dementia, potential racial/ethnic differences in dementia risk have not been explored in this population. We evaluated racial/ethnic differences in dementia and potential explanatory factors among older diabetic patients.

RESEARCH DESIGN AND METHODS

We identified 22,171 diabetic patients without preexisting dementia aged ≥60 years (14,546 non-Hispanic whites, 2,484 African Americans, 2,363 Latinos, 2,262 Asians, 516 Native Americans) from the Kaiser Permanente Northern California Diabetes Registry. We abstracted prevalent medical history (1 January 1996 to 31 December 1997) and dementia incidence (1 January 1998 to 31 December 2007) from medical records and calculated age-adjusted incidence densities. We fit Cox proportional hazards models adjusted for age, sex, education, diabetes duration, and markers of clinical control.

RESULTS

Dementia was diagnosed in 3,796 (17.1%) patients. Age-adjusted dementia incidence densities were highest among Native Americans (34/1,000 person-years) and African Americans (27/1,000 person-years) and lowest among Asians (19/1,000 person-years). In the fully adjusted model, hazard ratios (95% CIs) (relative to Asians) were 1.64 (1.30–2.06) for Native Americans, 1.44 (1.24–1.67) for African Americans, 1.30 (1.15–1.47) for non-Hispanic whites, and 1.19 (1.02–1.40) for Latinos. Adjustment for diabetes-related complications and neighborhood deprivation index did not change the results.

CONCLUSIONS

Among type 2 diabetic patients followed for 10 years, African Americans and Native Americans had a 40–60% greater risk of dementia compared with Asians, and risk was intermediate for non-Hispanic whites and Latinos. Adjustment for sociodemographics, diabetes-related complications, and markers of clinical control did not explain observed differences. Future studies should investigate why these differences exist and ways to reduce them.     

Pioglitazone Ameliorates Endothelial Dysfunction in Those with Impaired Glucose Regulation among the First-Degree Relatives of Type 2 Diabetes Mellitus Patients

Objective

To study the effects of pioglitazone on endothelial dysfunction of subjects with impaired glucose regulation (IGR) among the first-degree relatives of patients with type 2 diabetes mellitus (T2DM).

Subjects and Methods

The first-degree relatives of T2DM patients were screened with oral glucose test and IGR was diagnosed. IGR subjects whose blood glucose was still above the level after 1-month exercise were randomized to receive pioglitazone (15 mg/day) or vehicle for 12 weeks. Endothelial function was assessed as endothelium-dependent and -independent vasodilation. Blood nitric oxide (NO), blood pressure, body mass index, insulin and serum lipids were also measured. Area under the curve of glucose (AUC_glu) and insulin (AUC_INS), homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of β-cell function (HOMA-β) and early insulin secretion index (ΔI₃₀/ΔG₃₀) were calculated.

Results

After pioglitazone treatment, fasting plasma, 2-hour plasma glucose, triglyceride (TG), fasting insulin, AUC_glu, HOMA-β and HOMA-IR, 2-hour insulin, AUC_INS and ΔI₃₀/ΔG₃₀ decreased. Endothelium-dependent vasodilation and NO were significantly improved in the treatment group. Furthermore, the changes of endothelium-dependent vasodilation were negatively correlated with changes in AUC_INS but positively with NO and HOMA-β. Stepwise multivariate regression analysis showed that changes in NO and HOMA-β were both independent parameters for improvement of endothelial dysfunction.

Conclusion

Pioglitazone decreased blood glucose and TG, increased insulin sensitivity, and ameliorated endothelial dysfunction of IGR subjects among the first-degree relatives of T2DM patients. Increased NO production may be associated with the improvement of endothelial dysfunction.Key Words: Impaired glucose regulation, Endothelial dysfunction, Pioglitazone     

Relationship Between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth With Type 2 Diabetes: Baseline Findings From the TODAY Trial

OBJECTIVE

Children whose parents have diabetes are at increased risk for developing type 2 diabetes. This report assessed relationships between parental diabetes status and baseline demographics, anthropometrics, metabolic measurements, insulin sensitivity, and β-cell function in children recently diagnosed with type 2 diabetes.

RESEARCH DESIGN AND METHODS

The sample included 632 youth (aged 10–17 years) diagnosed with type 2 diabetes for <2 years who participated in the TODAY clinical trial. Medical history data were collected at baseline by self-report from parents and family members. Youth baseline measurements included an oral glucose tolerance test and other measures collected by trained study staff.

RESULTS

Youth exposed to maternal diabetes during pregnancy (whether the mother was diagnosed with diabetes prior to pregnancy or had gestational diabetes mellitus) were diagnosed at younger ages (by 0.6 years on average), had greater dysglycemia at baseline (HbA_1c increased by 0.3% [3.4 mmol/mol]), and had reduced β-cell function compared with those not exposed (C-peptide index 0.063 vs. 0.092). The effect of maternal diabetes on β-cell function was observed in non-Hispanic blacks and Hispanics but not whites. Relationships with paternal diabetes status were minimal.

CONCLUSIONS

Maternal diabetes prior to or during pregnancy was associated with poorer glycemic control and β-cell function overall but particularly in non-Hispanic black and Hispanic youth, supporting the hypothesis that fetal exposure to aberrant metabolism may have long-term effects. More targeted research is needed to understand whether the impact of maternal diabetes is modified by racial/ethnic factors or whether the pathway to youth-onset type 2 diabetes differs by race/ethnicity.     

Expression of Mesenchymal and α-Cell Phenotypic Markers in Islet β-Cells in Recently Diagnosed Diabetes

OBJECTIVE

Relative contributions of reversible β-cell dysfunction and true decrease in β-cell mass in type 2 diabetes remain unclear. Definitive rodent lineage-tracing studies have identified β-cell dedifferentiation and subsequent reprogramming to α-cell fate as a novel mechanism underlying β-cell failure. The aim was to determine whether phenotypes of β-cell dedifferentiation and plasticity are present in human diabetes.

RESEARCH DESIGN AND METHODS

Immunofluorescence colocalization studies using classical endocrine and mesenchymal phenotypic markers were undertaken using pancreatic sections and isolated islets from three individuals with diabetes and five nondiabetic control subjects.

RESULTS

Intraislet cytoplasmic coexpression of insulin and vimentin, insulin and glucagon, and vimentin and glucagon were demonstrated in all cases. These phenotypes were not present in nondiabetic control subjects.

CONCLUSIONS

Coexpression of mesenchymal and α-cell phenotypic markers in human diabetic islet β-cells has been confirmed, providing circumstantial evidence for β-cell dedifferentiation and possible reprogramming to α-cells in clinical diabetes.The relative contribution of reversible β-cell dysfunction and a true decrease in β-cell mass during the onset of and progression of type 2 diabetes have been hotly debated (1,2). Modest decreases in numbers of β-cells per islet and increases in β-cell apoptosis have been reported (3), but whether these are sufficient to account for the reduction in insulin secretory capacity remains unclear (4). Underpinned by recent rodent studies (5), a new hypothesis has been proposed whereby β-cell failure and increased α-cell function occur through dedifferentiation and reprogramming (6). We report, for the first time, expression of mesenchymal and α-cell phenotypic markers in human β-cells within intact islets of three individuals with diabetes.     

Declining ��-Cell Compensation for Insulin Resistance in Hispanic Women With Recent Gestational Diabetes Mellitus: Association with changes in weight, adiponectin, and C-reactive protein

OBJECTIVE

To identify factors associated with declining β-cell compensation for insulin resistance.

RESEARCH DESIGN AND METHODS

In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining β-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on β-cell compensation decline.

RESULTS

A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.

CONCLUSIONS

These results identify weight gain as the strongest factor associated with declining β-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.Type 2 diabetes is characterized by inadequate pancreatic β-cell compensation for chronic insulin resistance. Longitudinal studies in Pima Indians (1), Caucasian and African Americans (2,3), and Hispanic Americans (2,4) indicate that β-cell function declines on a background of chronic and often worsening insulin resistance as people progress from normal to impaired glucose tolerance and then to diabetes. Much is known about baseline factors that predict a relatively short time to diabetes—factors such as relatively high glucose levels, insulin resistance, and poor β-cell compensation for insulin resistance. Those factors could be important driving forces for the development of diabetes. They could also simply be markers of individuals closest to diabetes at the initiation of follow-up.Much less is known about the cause(s) of the progressive deterioration in β-cell function that leads to impaired glucose tolerance and diabetes. Declining β-cell function has been shown to be associated with weight gain in Pima Indians (5) and with increased fat in women with a family history of type 2 diabetes (6). Glucose and lipid toxicity have been suggested as causes of declining β-cell function (7), although data are lacking from humans to support such an effect over the years that it takes to develop diabetes.We conducted a longitudinal study investigating the pathogenesis of diabetes development in relatively young Hispanic women with recent gestational diabetes mellitus. We observed a progressive decline in β-cell compensation for insulin resistance that was attended by slowly rising glucose levels until β-cell compensation reached very low levels, at which time glucose levels rose to the diabetic range (4). The present analysis examines what baseline characteristics predict the decline in β-cell compensation for insulin resistance and the potential role and mechanism of weight gain and changes in circulating levels of adipokines and inflammatory markers during follow-up on declining β-cell compensation in this high-risk group.     

Pancreatic Steatosis and Its Relationship to β-Cell Dysfunction in Humans: Racial and ethnic variations

OBJECTIVE

To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans.

RESEARCH DESIGN AND METHODS

We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels.

RESULTS

Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R² = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R² = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R² = 0.32).

CONCLUSIONS

In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population.Diet-induced obesity (1) dramatically increases the risk—by >40-fold in certain populations (2)—for type 2 diabetes. A better understanding of the underlying mechanisms by which overnutrition-induced obesity causes diabetes could lead to the discovery of novel preemptive interventions.One putative mechanism is pancreatic steatosis with β-cell lipotoxicity (3). We define steatosis as high levels of triglyceride (TG) droplets in the cytosol of nonadipose cells and lipotoxicity as organ dysfunction caused by steatosis. It is important to note that cytosolic TG droplets are not toxic themselves but byproducts of their exaggerated metabolism are toxic and cause lipotoxic β-cell dysfunction, at least in animal models. In the Zucker diabetic fatty (ZDF) rat, a standard genetic model of obesity-related diabetes, pancreatic steatosis heralds the transition from insulin resistance with compensated hyperinsulinemia to β-cell failure and frank diabetes. In this model, excess of cytosolic TG marks excessive levels of ceramide and other toxic metabolites that activate inducible nitric oxide synthase to cause progressive β-cell apoptosis and failure (4–6). A key question is to what extent can this mechanistic hypothesis be translated to common obesity-related diabetes in humans?Localized proton magnetic resonance spectroscopy (¹H MRS) was developed as a noninvasive clinical research tool to conduct translational research testing steatosis and lipotoxicity hypotheses with precise in vivo quantification of cytosolic TGs within parenchymal cells of human skeletal muscle (7), liver (8), and heart muscle (9,10). This research has implicated skeletal muscle and liver steatosis as a cause of insulin resistance (11,12) and cardiac steatosis as a cause of obesity-related cardiomyopathy (13). More recently, we validated localized ¹H MRS as a measure of pancreatic TG levels (14). Insulin-secreting β-cells cannot be differentiated from non–insulin-secreting parenchymal cells of the human pancreas with ¹H MRS. However, in the ZDF rat, we documented that the accumulation of TGs in pancreatic tissue as measured by ¹H MRS closely parallels the development of β-cell failure both in time course and magnitude (14). We then demonstrated that pancreatic TG content is highly reproducible when healthy human subjects are studied repeatedly and that pancreatic TG level increases with increasing stages of human obesity and glucose intolerance even before the development of type 2 diabetes (14).The goal of this study was to test whether pancreatic TG constitutes a novel biomarker of early (prediabetic) β-cell dysfunction in human subjects representing the three major race/ethnic groups in the United States. African Americans and Hispanic Americans are known to have higher rates of type 2 diabetes than white Americans, even after adjustment for BMI (15). Moreover, Hispanic Americans are known to have higher rates of hepatic steatosis than other groups (8,12). However, ethnic differences in pancreatic steatosis—and its relationship to β-cell dysfunction—have not been studied previously.     

Elevated Rates of Diabetes in Pacific Islanders and Asian Subgroups: The Diabetes Study of Northern California (DISTANCE)

OBJECTIVE

We estimated the prevalence and incidence of diabetes among specific subgroups of Asians and Pacific Islanders (APIs) in a multiethnic U.S. population with uniform access to care.

RESEARCH DESIGN AND METHODS

This prospective cohort analysis included 2,123,548 adult members of Kaiser Permanente Northern California, including 1,704,363 with known race/ethnicity (white, 56.9%; Latino, 14.9%; African American, 8.0%; Filipino, 4.9%; Chinese, 4.0%; multiracial, 2.8%; Japanese, 0.9%; Native American, 0.6%; Pacific Islander, 0.5%; South Asian, 0.4%; and Southeast Asian, Korean, and Vietnamese, 0.1% each). We calculated age-standardized (to the 2010 U.S. population) and sex-adjusted diabetes prevalence at baseline and incidence (during the 2010 calendar year). Poisson models were used to estimate relative risks.

RESULTS

There were 210,632 subjects with prevalent diabetes as of 1 January 2010 and 15,357 incident cases of diabetes identified during 2010. The crude diabetes prevalence was 9.9% and the incidence was 8.0 cases per 1,000 person-years and, after standardizing by age and sex to the 2010 U.S. Census, 8.9% and 7.7 cases per 1,000 person-years. There was considerable variation among the seven largest API subgroups. Pacific Islanders, South Asians, and Filipinos had the highest prevalence (18.3, 15.9, and 16.1%, respectively) and the highest incidence (19.9, 17.2, and 14.7 cases per 1,000 person-years, respectively) of diabetes among all racial/ethnic groups, including minorities traditionally considered high risk (e.g., African Americans, Latinos, and Native Americans).

CONCLUSIONS

High rates of diabetes among Pacific Islanders, South Asians, and Filipinos are obscured by much lower rates among the large population of Chinese and several smaller Asian subgroups.Asians and Pacific Islanders (APIs) comprised 5% of the U.S. population in the 2010 Census, a 43% increase compared with the 2000 Census (1). The three largest API subgroups included people of Chinese (3.3 million), South Asian (2.8 million), or Filipino (2.6 million) ancestry. Most national health surveys before 2000 classified Asians as “other race” or, if recognized, combined them with Pacific Islanders; thus, the variation among API subgroups has been neglected.Epidemiologic studies and U.S. national surveillance report that Asians have a higher prevalence of type 2 diabetes relative to non-Hispanic whites, but lower than that of African Americans and Latinos (2,3). However, aggregation of API subgroups may preclude identifying those at particularly high risk for diabetes (4). A recent report from the U.S. National Health Interview Survey (NHIS) disaggregated API subgroups and found substantive differences in diabetes prevalence (3). Nonetheless, there is a paucity of published data on the prevalence and incidence of diabetes among API subgroups in the U.S (5,6).Through the Diabetes Study of Northern California (DISTANCE), we estimated racial/ethnic differences in the prevalence and incidence of diabetes in a large, multiethnic cohort of patients receiving care in an integrated health delivery system.     

Absence of disparities in the quality of primary diabetes care for South Asians and Chinese in an urban Canadian setting

OBJECTIVE

To examine whether quality of diabetes care is equitable for South Asian and Chinese patients in an urban Canadian setting.

RESEARCH DESIGN AND METHODS

Process and intermediate measures of quality of care were compared between 246 South Asians, 170 Chinese, and 431 patients from the general population with type 2 diabetes selected from 45 family physicians’ practices.

RESULTS

A total of 61% of Chinese achieved A1C ≤7.0% versus 45% of South Asians and 49% of the general population (P < 0.05). They were also more likely to achieve LDL cholesterol ≤2.0 mmol/L, while South Asians were more likely to achieve blood pressure ≤130/80. There was only one significant process of care deficiency: fewer foot examinations among South Asians (34 vs. 49% for the general population, P < 0.01).

CONCLUSIONS

Quality of diabetes care in a Canadian urban setting was equitable, with ethnic minorities somewhat more likely to achieve recommended targets than the general population.Racial and ethnic minority populations in the U.S. achieve worse health outcomes and have greater mortality than whites (1). The experience of ethnic minorities in Canada is different because of a publicly funded universal health care system that may mitigate some socioeconomic and insurance barriers to care. Canadian minorities also represent different ethnic groups, with the two largest being South Asians (from the Indian subcontinent) and Chinese (2). We examined quality of type 2 diabetes care in an urban family practice setting, comparing South Asians and Chinese with the general population.     

β-Cell Mass and Turnover in Humans: Effects of obesity and aging

OBJECTIVE

We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.

RESEARCH DESIGN AND METHODS

We examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.

RESULTS

β-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.

CONCLUSIONS

β-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.The incidence of type 2 diabetes increases with obesity and aging (1). There is a deficit in β-cell mass with increased β-cell apoptosis in type 2 diabetes (2). Although there are numerous studies of changes in β-cell mass and turnover in rodents, inevitably the data is much more limited in humans. As there is an increasing appreciation that regulation of β-cell mass in humans and rodents can be quite different, additional studies in humans, where possible, is important. In the current study, we addressed the following questions.First, is β-cell mass adaptively increased in obese humans, and if so, is this through increased β-cell replication as widely reported in rodents? It has been reported that β-cell mass increases with obesity in age-matched individuals but β-cell replication was not reported (3). Second, is β-cell apoptosis increased with obesity? The increased β-cell apoptosis in type 2 diabetes (2) has been ascribed to lipotoxicity, based on increased β-cell apoptosis in rodents with obesity due to deficient leptin signaling (4). Since the relative fat content (fat-to-acinar ratio) accumulates in the pancreas in humans with obesity (5), if this is sufficient to induce increased β-cell apoptosis, then it would be anticipated that humans with marked obesity would have increased β-cell apoptosis.Third, we questioned if β-cell mass adaptively decreases with aging, and if so, is this due to increased β-cell apoptosis? β-Cell function declines in humans with aging (6). The exocrine pancreas undergoes marked atrophy after 60 years of age, but there is limited data available about the changes in β-cell mass with aging, with one study reporting a marginal decline with age (3) but providing no measure of β-cell turnover.     

Effects of Leptin Replacement Therapy on Pancreatic β-Cell Function in Patients With Lipodystrophy

OBJECTIVE

Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16–20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy.

RESEARCH DESIGN AND METHODS

In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16–20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT.

RESULTS

There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance.

CONCLUSIONS

In contrast to the suppressive effects of leptin on β-cell function in rodents, 16–20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or β-cell function in leptin-deficient individuals with lipodystrophy.     

Effect of Exenatide,Sitagliptin, or Glimepiride on β-Cell Secretory Capacity in Early Type 2 Diabetes

OBJECTIVE

Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on β-cell secretory capacity, an in vivo measure of functional β-cell mass, early in the course of T2D.

RESEARCH DESIGN AND METHODS

We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIR_arg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIR_pot]), and 340 mg/dL (maximum arginine-induced insulin release [AIR_max]) hyperglycemic clamp conditions, in which AIR_max provides the β-cell secretory capacity.

RESULTS

The change in AIR_pot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIR_max (P = 0.1). Within each group, the primary outcome measure, AIR_max, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGR_min) was also increased with glimepiride treatment (P < 0.05), and the change in AGR_min trended higher with glimepiride than with exenatide (P = 0.06).

CONCLUSIONS

After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional β-cell mass as measured by β-cell secretory capacity, whereas glimepiride appeared to enhance β- and α-cell secretion.     

Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes

OBJECTIVE

We evaluated relationships of oral glucose tolerance testing (OGTT)–derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease.

RESEARCH DESIGN AND METHODS

A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria.

RESULTS

The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio −0.78 [95% CI −1.51 to −0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30–0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes.

CONCLUSIONS

Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.     

Preexisting Insulin Autoantibodies Predict Efficacy of Otelixizumab in Preserving Residual β-Cell Function in Recent-Onset Type 1 Diabetes

OBJECTIVE

Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose.

RESEARCH DESIGN AND METHODS

In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay.

RESULTS

At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA⁺ participants with relatively preserved β-cell function [≥25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome.

CONCLUSIONS

There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.     

Independent effect of ethnicity on glycemia in South Asians and white Europeans

OBJECTIVE

HbA_1c levels are higher in most ethnic groups compared with white Europeans (WEs) independent of glycemic control. This comparison has not been performed between South Asians (SAs) and WEs. We analyzed the independent effect of ethnicity on HbA_1c and fasting and 2-h plasma glucose (FPG and 2hrPG, respectively) between these groups.

RESEARCH DESIGN AND METHODS

Analysis of the ADDITION-Leicester study, in which 4,688 WEs and 1,352 SAs underwent oral glucose tolerance testing, HbA_1c, and other risk factor measurements.

RESULTS

Significant associations with HbA_1c included ethnicity, FPG, 2hrPG, and homeostasis model assessment of β-cell function (P < 0.001); age and sex (P < 0.01); and fasting insulin and potassium (P < 0.05). After adjusting for these and other risk factors, SAs demonstrated higher HbA_1c (6.22 and 6.02%, mean difference 0.20%, 0.10–0.30, P < 0.001), FPG (5.15 and 5.30 mmol/L, mean difference 0.15 mmol/L, 0.09–0.21, P < 0.001), and 2hrPG (5.82 and 6.57 mmol/L, mean difference 0.75 mmol/L, 0.59–0.92, P < 0.001) compared with WEs, respectively.

CONCLUSIONS

HbA_1c, FPG, and 2hrPG levels were higher in SAs independent of factors affecting glycemic control.Glycated hemoglobin (HbA_1c) is now recommended as a diagnostic tool for detecting type 2 diabetes, alongside fasting and 2-h plasma glucose (FPG and 2hrPG, respectively), and remains the standard test for monitoring disease progression (1). Previous studies demonstrate HbA_1c values are higher in some black and minority ethnic groups compared with white Caucasians independent of glycemic control or factors that differ between ethnic groups (2–5). These studies suggest HbA_1c levels are higher in African Americans by 0.2–0.4%, in Hispanics by 0.1–0.3%, and in Southeast Asians by 0.2–0.3% (2–5). Because this analysis has not been performed in South Asians (people of Indian, Pakistani, and Bangladeshi origin), our aim was to evaluate the independent effect of ethnicity on glycemia among South Asians and white Europeans and to quantify the magnitude of any differences.     

β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission

OBJECTIVE

Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize β- and α-cell functions in Africans with KPD during remission.

RESEARCH DESIGN AND METHODS

We characterized β- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping.

RESULTS

Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin.

CONCLUSIONS

Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that β- and α-cell dysfunctions both contribute to the pathophysiology of KPD.Ketosis-prone atypical diabetes (KPD) is a frequent specific subtype of diabetes in African Americans and sub-Saharan Africans (1–3). Patients with KPD present at onset with acute hyperglycemia and ketosis or ketoacidosis owing to an insulin secretory deficiency, but autoimmune markers against islet β-cells are absent (4–6). A prolonged insulin-free near-normoglycemic remission phase frequently follows the acute phase after insulin treatment and is associated with a significant recovery of the insulin secretory function (4,7,8). These observations have suggested that the blunting in insulin secretion at disease onset may be due to a functional disorder of β-cells rather than to cell destruction. We previously hypothesized that KPD is a subtype of type 2 diabetes with acute onset at diagnosis as the result of an environmental triggering factor, such as a viral infection, that severely impairs glucose-stimulated insulin secretion and favors ketogenesis (9). KPD patients display insulin resistance at the level of muscles, liver, and adipose tissue during remission (10). However, maximal insulin secretory capacity and surrogates of α-cell mass have not been evaluated, and whether α-cell dysfunction also contributes to the pathophysiology of KPD, as described in type 2 diabetes (11–14) is not known.In the current study, we therefore measured early insulin secretion in response to oral glucose, dose-response insulin secretion to intravenous glucose, and maximum secretory response to arginine combined with glucose (glucose potentiation of arginine-induced insulin secretion) in Africans with KPD during near-normoglycemic remission compared with control subjects of the same ethnic background. Function of α-cells was assessed by measuring glucagon in response to glucose, insulin, and arginine.     

Heterogeneity of diabetes outcomes among asians and pacific islanders in the US: the diabetes study of northern california (DISTANCE)

OBJECTIVE

Ethnic minorities with diabetes typically have lower rates of cardiovascular outcomes and higher rates of end-stage renal disease (ESRD) compared with whites. Diabetes outcomes among Asian and Pacific Islander subgroups have not been disaggregated.

RESEARCH DESIGN AND METHODS

We performed a prospective cohort study (1996–2006) of patients enrolled in the Kaiser Permanente Northern California Diabetes Registry. There were 64,211 diabetic patients, including whites (n = 40,286), blacks (n = 8,668), Latinos (n = 7,763), Filipinos (n = 3,572), Chinese (n = 1,823), Japanese (n = 951), Pacific Islanders (n = 593), and South Asians (n = 555), enrolled in the registry. We calculated incidence rates (means ± SD; 7.2 ± 3.3 years follow-up) and created Cox proportional hazards models adjusted for age, educational attainment, English proficiency, neighborhood deprivation, BMI, smoking, alcohol use, exercise, medication adherence, type and duration of diabetes, HbA_1c, hypertension, estimated glomerular filtration rate, albuminuria, and LDL cholesterol. Incidence of myocardial infarction (MI), congestive heart failure, stroke, ESRD, and lower-extremity amputation (LEA) were age and sex adjusted.

RESULTS

Pacific Islander women had the highest incidence of MI, whereas other ethnicities had significantly lower rates of MI than whites. Most nonwhite groups had higher rates of ESRD than whites. Asians had ~60% lower incidence of LEA compared with whites, African Americans, or Pacific Islanders. Incidence rates in Chinese, Japanese, and Filipinos were similar for most complications. For the three macrovascular complications, Pacific Islanders and South Asians had rates similar to whites.

CONCLUSIONS

Incidence of complications varied dramatically among the Asian subgroups and highlights the value of a more nuanced ethnic stratification for public health surveillance and etiologic research.Individuals of Asian origin comprise ~4.7% of the U.S. population (1), and people from the Pacific Islands comprise another 0.3% of the population (2). It has been estimated that by the year 2050, 10% of the U.S. population will be of Asian or Pacific Islander ancestry (3). Yet, there is little systematic data collection on Asian Americans and Pacific Islanders and almost no long-term outcome studies among these ethnic groups by country of origin.Both Asians (4,5) and Pacific Islanders (6) have been recognized as having higher rates of type 2 diabetes than whites and other ethnic minority groups in the U.S. (3). Explanations for this higher diabetes prevalence have included cultural, socioeconomic, behavioral, and genetic factors (4,5). However, among those with diabetes, it is unclear whether Asians and Pacific Islanders have similar incidence of complications relative to whites or other ethnic groups. In previous diabetes research, data for Asians and Pacific Islanders was aggregated, and this heterogeneous group had a significantly lower incidence of cardiovascular disease outcomes and lower-extremity amputations (LEAs) and higher end-stage renal disease (ESRD) rates over 2 years of follow-up compared with whites (7). However, the insufficient numbers of individuals in each ethnic category and short follow-up time precluded examination of specific subgroups.We disaggregated data from East Asians, South Asians, Filipinos, and Pacific Islanders from a large, diverse cohort of diabetic patients enrolled in the Kaiser Permanente managed care organization in northern California and determined the incidence of major diabetes complications after ~7 ± 3 years of follow-up or 413,500 person-years. We compared the risk of each complication in four separate Asian groups and Pacific Islanders with that in whites, African Americans, and Latinos after adjusting for several potential explanatory factors. We hypothesized that the incidence of complications will differ significantly between each specific Asian and Pacific Islander subgroup compared with whites, and aggregation of all Asians together obscures this variation.     

Insulin Resistance and Left Ventricular Mass in Non-Diabetic Hemodialysis Patients

Background

Insulin resistance (IR) is frequently recognized in patients with uremia, and it is thought that IR has a basic role in the pathogenesis of cardiovascular disease.

Objective

To evaluate the effect of IR on cardiovascular risk in non-diabetic patients receiving hemodialysis (HD).

Methods

We performed a cross-sectional observational study that comprised 186 non-diabetic patients receiving HD (95 men; mean [SD] age, 46.4 [10.8] years; age range, 35–60 years) who had been receiving HD for 7.3 (3.5) years. Demographic variables and laboratory values were recorded. Insulin resistance was determined using the Homeostatic Model Assessment (HOMA), and the left ventricular mass index (LVMI) was calculated via echocardiography.

Results

According to HOMA-IR levels, patients were categorized as having IR (HOMA-IR score ≥2.5; n = 53) or not having IR (HOMA-IR score <2.5; n = 133). Insulin resistance was determined in 28.4% of study patients. Compared with the non-IR group, the IR group had been receiving HD longer; had greater body mass index; and had higher serum creatinine, uric acid, triglyceride, insulin, and C-reactive protein concentrations, leukocyte count, and LVMI (P < 0.05). Patients with increased LVMI had significantly higher body mass index, systolic blood pressure, serum cholesterol and C-reactive protein concentrations, and HOMA score. At multivariate analysis, systolic blood pressure (β = 0.22; P = 0.03) and HOMA score (β = 0.26; P = 0.01) affected LVMI.

Conclusions

Insulin resistance and hypertension are independent risk factors for left ventricular hypertrophy in non-diabetic patients with uremia who are receiving HD. Further studies are needed to indicate the benefits of improving IR for cardiovascular mortality in this subgroup of patients with uremia.Key words: hemodialysis, insulin resistance, ventricular hypertrophy     

Association of Vitamin D With Insulin Resistance and ��-Cell Dysfunction in Subjects at Risk for Type 2 Diabetes

OBJECTIVE

To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and β-cell dysfunction in 712 subjects at risk for type 2 diabetes.

RESEARCH DESIGN AND METHODS

Serum 25(OH)D was determined using a chemiluminescence immunoassay. Insulin sensitivity/resistance were measured using the Matsuda insulin sensitivity index for oral glucose tolerance tests (IS_OGTT) and homeostasis model assessment of insulin resistance HOMA-IR. β-Cell function was determined using both the insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2).

RESULTS

Linear regression analyses indicated independent associations of 25(OH)D with IS_OGTT and HOMA-IR (β = 0.004, P = 0.0003, and β = −0.003, P = 0.0072, respectively) and with IGI/IR and ISSI-2 (β = 0.004, P = 0.0286, and β = 0.003, P = 0.0011, respectively) after adjusting for sociodemographics, physical activity, supplement use, parathyroid hormone, and BMI.

CONCLUSIONS

Vitamin D may play a role in the pathogenesis of type 2 diabetes, as 25(OH)D concentration was independently associated with both insulin sensitivity and β-cell function among individuals at risk of type 2 diabetes.Emerging evidence suggests a role for vitamin D in the etiology of type 2 diabetes (1). However, associations of vitamin D with insulin resistance (IR) and especially β-cell dysfunction have been inconsistent (2–7). Therefore, our objective was to assess the association of serum vitamin D concentration with IR and β-cell dysfunction in a large, ethnically-diverse, North American cohort at risk of type 2 diabetes.     

Influence of Adiposity on Insulin Resistance and Glycemia Markers Among U.K. Children of South Asian,Black African-Caribbean,and White European Origin: Child Heart and Health Study in England

OBJECTIVE

Ethnic differences in type 2 diabetes risk between South Asians and white Europeans originate before adult life and are not fully explained by higher adiposity levels in South Asians. Although metabolic sensitivity to adiposity may differ between ethnic groups, this has been little studied in childhood. We have therefore examined the associations among adiposity, insulin resistance, and glycemia markers in children of different ethnic origins.

RESEARCH DESIGN AND METHODS

Cross-sectional study of 4,633 9- to 10-year-old children (response rate 68%) predominantly of South Asian, black African-Caribbean, and white European origin (n = 1,266, 1,176, and 1,109, respectively) who had homeostasis model assessments of insulin resistance (HOMA-IR), glycemia markers (HbA_1c and fasting glucose), and adiposity (BMI, waist circumference, skinfold thicknesses, and bioimpedance [fat mass]).

RESULTS

All adiposity measures were positively associated with HOMA-IR in all ethnic groups, but associations were stronger among South Asians compared to black African-Caribbeans and white Europeans. For a 1-SD increase in fat mass percentage, percentage differences in HOMA-IR were 37.5% (95% CI 33.3–41.7), 29.7% (25.8–33.8), and 27.0% (22.9–31.2), respectively (P interaction < 0.001). All adiposity markers were positively associated with HbA_1c in South Asians and black African-Caribbeans but not in white Europeans; for a 1-SD increase in fat mass percentage, percentage differences in HbA_1c were 0.04% (95% CI 0.03–0.06), 0.04% (0.02–0.05), and 0.02% (−0.00 to 0.04), respectively (P interaction < 0.001). Patterns for fasting glucose were less consistent.

CONCLUSIONS

South Asian children are more metabolically sensitive to adiposity. Early prevention or treatment of childhood obesity may be critical for type 2 diabetes prevention, especially in South Asians.The prevalence of type 2 diabetes has been rising, both in the U.K. population (1) and worldwide (2,3). In the U.K., there are marked ethnic differences in the risks of type 2 diabetes, which are particularly high among South Asians and to a lesser extent black African-Caribbeans (4); increased type 2 diabetes risks are also apparent in these ethnic groups in the U.S. (5,6). Recent evidence suggests that ethnic differences in risks of type 2 diabetes are apparent in childhood, with higher levels of insulin resistance (a key precursor of type 2 diabetes), glycated hemoglobin (HbA_1c), and (less consistently) fasting blood glucose concentrations observed in U.K. South Asians and to a lesser extent black African-Caribbeans compared with white Europeans by the age of 10 years (7).Excess body fat (adiposity) is an important independent risk factor for the development of type 2 diabetes and insulin resistance both in adults (8,9) and children (10). However, the role of adiposity in these ethnic differences in type 2 diabetes is complex. In South Asian adults, it is well-recognized that BMI underestimates adiposity (11) and that body fat levels (particularly of central body fat) are higher than those of white Europeans (10,12–14). However, in most studies, adjusting for the higher body fat levels (usually assessed using skinfold thickness or waist and hip circumferences) has not accounted for the higher risks of diabetes and insulin resistance observed in South Asians (13,15–17). It has also been observed that the risks of diabetes, insulin resistance, and cardiovascular disease emerge at lower levels of adiposity (particularly BMI) in South Asian populations and that their associations with adiposity are stronger than those in white Europeans (13,17). We have previously shown in U.K. South Asian children that higher insulin and HbA_1c levels do not appear to be explained by higher adiposity levels (7,18). In a preliminary study, we also showed that insulin resistance in U.K. South Asian children may be more sensitive to adiposity than in white Europeans (18). However, this latter observation needs to be substantiated in larger scale studies in which insulin resistance, glycemia marker levels, and a range of adiposity markers are assessed in children from the relevant ethnic groups.We have therefore examined the cross-sectional associations among adiposity, insulin resistance, and glycemia markers in a study of ∼5,000 children of South Asian and white European origin aged 9 to 10 years; we also report on associations among children of black African-Caribbean origin. We hypothesized that metabolic sensitivity to adiposity would be greater in South Asians than white Europeans. Several adiposity markers were assessed, including measures based on skinfold thickness and bioimpedance, which provide robust measures of adiposity in this multiethnic population (19), as well as BMI and waist circumference. We have also included data on leptin, an adipokine with circulating levels that are strongly correlated with total body fat percentage (20). Because other studies have suggested that lower lean mass may be an important determinant of insulin resistance in young South Asian men (21), we also report on the influence of fat-free mass (FFM) on insulin resistance and glycemia.