Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes(T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models...     

Preventing β-cell loss and diabetes with calcium channel blockers

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.     

Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT

OBJECTIVE

ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of β-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments.

RESEARCH DESIGN AND METHODS

Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT.

RESULTS

Measures of β-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of β-cell function in those who failed to maintain adequate glucose control with initial monotherapy.

CONCLUSIONS

The favorable combined changes in β-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.In the UK Prospective Diabetes Study (UKPDS), a progressive decline in β-cell function was the major determinant of loss of glycemic control over time in type 2 diabetes (1). However, differential effects of diet, sulfonylurea, and metformin on insulin sensitivity and β-cell function did not yield substantive differences in the rates of increase in glycated hemoglobin (1).Subsequently, thiazolidinediones were introduced that primarily improve insulin sensitivity in the peripheral tissues (2), while also affecting β-cell function by reducing the demand to synthesize and release insulin. In contrast, the biguanide metformin acts primarily to reduce hepatic glucose production, whereas the sulfonylureas stimulate insulin release by binding to their receptor on the β-cell (2).Given these different mechanisms of action, A Diabetes Outcome Progression Trial (ADOPT) was designed to assess whether initial monotherapy with the thiazolidinedione rosiglitazone could slow the rate of decline of β-cell function in type 2 diabetes and associated loss-of-glucose control, relative to metformin or sulfonylurea (glyburide) (3). In ADOPT, rosiglitazone provided lower rates of monotherapy failure and lower levels of fasting plasma glucose and glycated hemoglobin, yielding superior durability of glycemic control than metformin or glyburide (4).Measures of insulin sensitivity and β-cell function determined from fasting and 30-min samples during an oral glucose tolerance test (OGTT) allowed examination of mechanisms by which each agent affected glycemic outcomes. Herein, changes over time for these measures are compared among the three treatment groups in the full cohort and separately among those who either successfully completed or failed initially assigned monotherapy over a period of 4 years. Joint vector plots are used to display concomitant changes in secretory response and insulin sensitivity over time with each therapy.     

Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual β-cell function

OBJECTIVE

To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function.

RESEARCH DESIGN AND METHODS

Eight type 1 diabetic patients with (T1D+), eight without (T1D−) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.

RESULTS

Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D− patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D− patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.

CONCLUSIONS

Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.At time of diagnosis and during the first year, prevalence of residual β-cell function in patients with type 1 diabetes is nearly 100% (1,2). After alleviation of initial hyperglycemia with exogenous insulin, patients enter a remission period with improved β-cell function, where insulin treatment can be paused in up to 20–30% of the patients without loss of target glycemic control (3). Persistence of residual insulin secretion is associated with reduced risk of ketosis (4), lower HbA_1c levels (5), lower insulin doses, less risk of hypoglycemia, and reduced long-term complications (2,6). However, after disease duration of 5–10 years, the prevalence of residual β-cell function has declined to about 15% (2). Even though lack of insulin is considered to be the most important factor for the hyperglycemia in type 1 diabetic patients, other metabolic disturbances may also play a role: the glucagon response to carbohydrate and protein ingestion has been shown to be abnormal (7) and there is evidence that postprandial hyperglycemia is because of lack of insulin as well as inappropriately elevated glucagon levels (8,9). The gut hormone, glucagon-like peptide 1 (GLP-1), reduces glucagon levels, increases insulin secretion (10), and inhibits gastric emptying rate (GE), thereby reducing postprandial glucose excursions (11). The insulinotropic and the glucagonostatic properties of GLP-1 are glucose dependent (12), and exogenous GLP-1, therefore, does not produce hypoglycemia. Several studies have found lowering of fasting and postprandial glucose by GLP-1 or GLP-1 agonists in type 1 diabetic patients with (13–15) as well as without (16–19) residual β-cell function. Some studies suggested that the glucose lowering effect was because of the enhancement of insulin sensitivity (19), whereas others concluded that delay of gastric emptying (13,14) or reduction of glucagon levels (17) was the most important mechanism. In animal studies, treatment with GLP-1 or GLP-1 agonists has been shown to delay diabetes development or reverse recent onset diabetes in NOD mice (20), ascribed to an improved function of existing β-cells rather than through increments in β-cell mass. However, there is also evidence that GLP-1, in combination with gastrin, increases β-cell mass and restores normoglycemia in recent onset diabetic NOD mice (21) and that GLP-1 combined with gastrin is able to expand β-cell mass of human islets implanted under the renal capsule of immunodeficient diabetic NOD mice (22). In freshly isolated human islets, GLP-1 has been reported to inhibit β-cell apoptosis (23). However, in C-peptide–positive subjects with longstanding type 1 diabetes treated with exenatide for 6 to 9 months with or without daclizumab, insulin dose was significantly reduced, primarily because of the reduction of prandial insulin, but β-cell function was not improved (15). Four weeks of treatment with vildagliptin (a DPP-4 inhibitor that increases endogenous GLP-1 levels) in 11 well-controlled type 1 diabetic patients with longstanding disease decreased postmeal glucagon and glucose levels (24), and in adolescents with minimal or no endogenous insulin secretion treated with exenatide, postprandial glucose excursions were reduced despite 20% reduction of insulin dose (25). Therefore, GLP-1–based therapies have potential for treatment of type 1 diabetes alone or—more likely—in combination with insulin.Because of controversies regarding secretion of incretin hormones in type 1 diabetes (26,27), assessment of the meal-related GLP-1 secretory responses in patients with diabetes is of interest (28). We therefore studied incretin secretion as well as the antidiabetic actions of both endogenously secreted and exogenously infused GLP-1 during a mixed meal in type 1 diabetic patients with and without residual β-cell function.     

Progressive erosion of β-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes

OBJECTIVE

A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes.

RESEARCH DESIGN AND METHODS

Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests.

RESULTS

During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity.

CONCLUSIONS

There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.Type 1 diabetes is an autoimmune disease resulting from the destruction of pancreatic insulin-producing β-cells. The NOD mouse is the most commonly used rodent model of the disease. Studies in this mouse strain have led to interventions that have been translated to clinical investigations with human type 1 diabetic patients (1–5). However, intervening at the right therapeutic window is critical to the efficacy of certain therapies. For example, anti-mouse thymocyte globulin can delay or reverse diabetes in NOD only when used in the late prediabetes stage or at onset of the disease (6).Islet autoimmunity can be identified in the prediabetic stage. Specifically, in NOD mice, insulin autoantibodies can be detected as early as at 3 weeks of age (7). However, as in humans, autoantibody positivity can be transient as well as observed in nonprogressors (8,9). Therefore, markers of β-cell mass and function are needed to identify progression from the onset of islet autoimmunity to and through the stages of prediabetes.Previous cross-sectional studies have demonstrated decreased first-phase insulin secretion in NOD females at different ages. Using pancreatic perfusion, Kano et al. (10) documented that NOD mice maintain normal fasting glucose even though a significant decrease was measured in first-phase insulin response (FPIR) to glucose. In these studies, increased fasting glucose and loss of FPIR was associated with the degree of insulitis. In cross-sectional studies using intravenous glucose tolerance test, Reddy et al. (11) showed an age-related progressive decline in FPIR to glucose. In another cross-sectional study using in situ pancreas perfusion, Sreenan et al. (12) reported progressive decreases in glucose- and arginine-stimulated insulin secretion in NOD females at 8, 13, and 18 weeks of age. Although single-point analyses were performed, there have not been reports involving sequential analysis of single mice over time to confirm this progression. In this study, we sought to determine whether similar metabolic signatures exist in both humans and in prediabetic NOD mice.     

Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.     

Decreased insulin secretion in type 2 diabetes: a problem of cellular mass or function?

Type 2 diabetes is characterized by diminished or inappropriate secretion of insulin, which could be a defect of either islet cell function or beta-cell mass. Quantitation of islet cell populations in postmortem pancreas demonstrates little change of beta-cell mass in type 2 diabetes. Reduction of islet cell mass (up to 30%) is associated largely with islet amyloid deposition, and the degree of amyloidosis is independent of the duration of the disease. Insulin secretory capacity is dependent on both function and mass of cells. beta-Cell secretion is heterogeneous; increasing glucose concentrations result in recruitment of beta-cells into the secretory pool, indicating a large reserve of secretory capacity that can be recruited in insulin resistant conditions. The Starling curve of islet function describes the relationship of insulin secretion to increasing levels of insulin resistance and hyperglycemia in type 2 diabetes. Longitudinal studies in Macaca mulatta monkeys show that insulin resistance is accompanied by increased islet mass and onset of diabetes is associated with deposition of amyloid and reduction of beta-cells. Increasing the function of unresponsive beta-cells rather than the mass of cells may be a more effective therapeutic target for type 2 diabetes.     

Can clinical factors estimate insulin resistance in type 1 diabetes?

An insulin resistance syndrome (IRS) score was developed based on clinical risk factors in adults with childhood-onset type 1 diabetes in the Epidemiology of Diabetes Complications (EDC) Study and was validated using euglycemic-hyperinsulinemic clamp studies. Hypertension, waist-to-hip ratio (WHR), triglyceride and HDL cholesterol levels, family history of type 2 diabetes, and glycemic control were risk factors used to define the score. A score of 1 (lowest likelihood IRS) to 3 (highest likelihood IRS) was assigned for each risk factor. Eligible subjects (n = 24) were recruited from the EDC cohort based on tertile of IRS score. Subjects received an overnight insulin infusion to normalize glucose levels, then underwent a 3-h euglycemic-hyperinsulinemic (60 mU x m(-2) x min(-1)) clamp. Glucose disposal rate (GDR) was determined during the last 30 min of the clamp. The GDR differed significantly by IRS group (9.65 +/- 2.99, 8.02 +/- 1.39, and 5.68 +/- 2.16 mg x kg(-1) x min(-1), P < 0.01). The GDR was inversely correlated with the IRS score (r = -0.64, P < 0.01). Using linear regression, the combination of risk factors that yielded the highest adjusted r2 value (0.57, P < 0.001) were WHR, hypertension, and HbA1. This study found that clinical risk factors can be used to identify subjects with type 1 diabetes who are insulin resistant, and it provides validation of a score based on clinical factors to determine the extent of insulin resistance in type 1 diabetes. This score will be applied to the entire EDC population in future studies to determine the effect of insulin resistance on complications.     

mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic β-cell

OBJECTIVE

To investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice.

RESEARCH DESIGN AND METHODS

NOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2^a allele (NOD.mt^ALR) were created and compared with standard NOD (carrying the mt-Nd2^c allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive splenic leukocyte transfers, as well as by adoptive transfer of diabetogenic T-cell clones. β-Cell lines derived from either the NOD (NIT-1) or the NOD.mt^ALR (NIT-4) were also created to compare their susceptibility to cytolysis by diabetogenic CD8⁺ T-cells in vitro.

RESULTS

NOD mice differing at this single SNP developed spontaneous or adoptively transferred diabetes at comparable rates and percentages. However, conplastic mice with the mt-Nd2^a allele exhibited resistance to transfer of diabetes by the CD4⁺ T-cell clone BDC 2.5 as well as the CD8⁺ AI4 T-cell clones from T-cell receptor transgenic animals. NIT-4 cells with mt-Nd2^a were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells.

CONCLUSIONS

Conplastic introduction into NOD mice of a variant mt-Nd2 allele alone was not sufficient to prevent spontaneous autoimmune diabetes. Subtle nonhematopoietic type 1 diabetes resistance was observed during adoptive transfer experiments with T-cell clones. This study confirms that genetic polymorphisms in mitochondria can modulate β-cell sensitivity to autoimmune T-cell effectors.Type 1 diabetes is a complex disease regulated by multiple genetic, metabolic, and environmental factors. In both human and animal models, genetic contributions to autoimmune diabetes have been linked to loci both in the nuclear as well as in mitochondrial genome (mtDNA) (1–5). While mtDNA polymorphisms can severely impair energy metabolism and lead to diabetes (6), only a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-ND2) has been associated with autoimmune diabetes in NOD mice and in humans (3–5).Crossing the genetically related diabetes-prone NOD/ShiLt and diabetes-resistant alloxan resistant (ALR)/Lt mouse models (7,8) we previously mapped ALR-derived resistance against spontaneous diabetes to three nuclear loci and, by reciprocal outcrosses, to a mtDNA SNP in mt-Nd2 (4). ALR mice were selected for resistance to alloxan, a free radical generator and selective β-cell toxin (7). This selection process resulted in mice with unusually elevated cellular defenses both systemically and at the islet level, providing resistance to both free radicals (9,10) and autoimmune effectors (5,11). In an additional genetic study to define loci or genes that provided diabetes resistance at the β-cell level, the ALR-derived mt-Nd2^a was significantly associated with resistance against alloxan-induced diabetes (9,12).Sequence analysis of mtDNA revealed a SNP that distinguishes the ALR strain from NOD and all other strains whose mtDNA has been sequenced (5,13). ALR mice harbor a C to A nucleotide transversion and an amino acid substitution from leucine to methionine (5). In humans, there is a corresponding C to A SNP in mt-ND2 resulting in an identical amino acid substitution. The human mt-ND2^c allele has also been reported to persist at a higher frequency in patients than control subjects (3). Allelism in mt-ND2^a was initially proposed to alter scavenging of reactive oxygen species (ROS) (3). However, our studies did not substantiate a role in ROS dissipation, but rather we have established that the resistance allele of this gene reduces basal mitochondrial ROS production by ∼30% (14,15). Hence, it might be predicted that this change in mitochondrial ROS may significantly alter β-cell death. In the present study, we confirm that mt-Nd2^a protects against β-cell death mediated by single T-cell clones but not against the full array of autoimmune effector mechanisms.     

Renal function in children with β-thalassemia major and thalassemia intermedia

In beta-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies demonstrating proteinuria, aminoaciduria, low urine osmolality, and excess secretion of the tubular damage markers, such as urinary N-acetyl-D-glucosaminidase (U(NAG)) and beta2 microglobulin, in patients with thalassemia. The object of this study was to analyze renal tubular and glomerular function in pediatric patients with beta-thalassemia and to correlate the renal findings to iron overload. Thirty-seven patients with beta-thalassemia major and 11 with thalassemia intermedia were studied. Twelve children without iron metabolism disorders or renal diseases served as a control group. No difference in blood urea nitrogen (BUN), serum creatinine, creatinine clearance, electrolytes, fractional excretion of sodium and potassium, and tubular phosphorus reabsorption was found. Serum uric acid was equal in the two groups, but its urine excretion was significantly higher in the thalassemic group. U(NAG) and U(NAG) to creatinine ratio (U(NAG/CR)) were elevated in all patients with thalassemia compared with the control group (p < 0.001) and were directly correlated to the amount of transfused iron but not to actual ferritin level. We found that renal tubular function is impaired in children with beta- thalassemia major and intermedia. It is not known whether these functional abnormalities would have any long-term effects on the patients. Further studies are needed, and means of preventing these disturbances should be sought.     

Renal function in pediatric patients with β-thalassemia major

In patients with β-thalassemia major, the most important cause of mortality and morbidity is organ failure due to deposits of iron.. In this study, the nature of the kidney injury and possible pathogenetic factors were investigated. Seventy children with β-thalassemia major and 14 age and sex-matched healthy children were involved in the study. Blood and timed urine samples were obtained for hematological and biochemical tests. The mean values of blood urea nitrogen (BUN), serum creatinine, creatinine clearance, serum sodium, urine osmolality, fractional excretion of sodium, potassium, and uric acid were not statistically different between the groups. Serum levels of potassium, phosphorus, and uric acid and the urine volume, high urinary protein to creatinine (U_P/Cr), urinary N-acetyl-β-d-glucosaminidase to creatinine (U_NAG/Cr), and urinary malondialdehyde to creatinine, (U_MDA/Cr) and the tubular phosphate reabsorption (TRP) values were statistically different between two groups (P<0.05). Increased serum levels of potassium, phosphorus, and uric acid in the patient group were attributed to the rapid erythrocyte turnover. The presence of high U_P/Cr, U_NAG/Cr and U_MDA/Cr ratios shows that in these patients with proximal renal tubular damage may be secondary to oxidative lipid peroxidation mediated by the iron overload. Received: 30 September 1999 / Revised: 19 May 2000 / Accepted: 22 May 2000     

β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes

Type 2 diabetes(T2DM) is characterized by insulin resistance and β-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2 DM, T2 DM never develops unless β-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of β-cell functional mass is an essential component of the pathophysiology of T2 DM, implying that β-cell deficit is a common feature of both type 1 and type 2 diabetes. β-cell dysfunction is present at the diagnosis of T2 DM and progressively worsens with disease duration. β-cell dysfunction is associated with worseningof glycemic control and treatment failure; thus, it is important to preserve or recover β-cell functional mass in the management of T2 DM. Since β-cell regenerative capacity appears somewhat limited in humans, reducing β-cell workload appears to be the most effective way to preserve β-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2 DM. This review summarizes the current knowledge on β-cell functional mass in T2 DM and discusses the treatment strategy for T2 DM.