Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

New therapeutic approaches for type 1 diabetes: Disease-modifying therapies

It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.     

Diabetes mellitus: new drugs for a new epidemic

The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties.     

不同胃肠道重建方式对2型糖尿病患者术后胰岛功能的影响

目的探讨不同胃肠道重建方式对2型糖尿病患者术后胰岛功能的影响。方法对23例胃癌合并2型糖尿病患者的临床资料进行回顾性分析．并按消化道重建方式的不同分为BillrothⅠ式组（13例）和胃肠旁路组（10例。其中毕Ⅱ式吻合4例,Roux—en—Y吻合6例）。行口服糖耐量试验（OGTr）．采用电化学发光法检测血清胰岛素水平．采用葡萄糖氧化酶法测定血糖．采用稳态模式评估法评价胰岛素抵抗指数和胰岛素分泌指数。结果胃肠旁路术组和BillorthⅠ式组术后糖尿病好转率分别为90％（9／10）和23％（3／13）,差异有统计学意义（P〈0．01）。与术前相比,胃肠旁路组术后糖化血红蛋白A1c和糖化血红蛋白HbAl显著降低（P〈0．01）．而BillrothⅠ式组则无明显改善（P〉0．05）。OGTF结果显示,胃肠旁路组空腹血糖及及糖负荷后各个时间点的血糖水平均显著低于BillrothⅠ式组：在糖负荷后30min和60min．胃肠旁路术组胰岛素水平和胰岛素释放指数明显高于BillrothⅠ式组（均P〈0．05）。胃肠旁路组的胰岛素分泌指数和早期胰岛素分泌反应同样明显高于BillrothⅠ式组。结论采用胃肠旁路术进行胃切除术后消化道重建．可有效控制2型糖尿病并明显改善术后胰岛功能。     

Oxidative stress,insulin resistance,dyslipidemia and type 2 diabetes mellitus

Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus(T2DM) and this appears to underlie the development of cardiovascular disease,T2 DM and diabetic complications.Increased oxidative stress appears to be a deleterious factor leading toinsulin resistance,dyslipidemia,β-cell dysfunction,impaired glucose tolerance and ultimately leading to T2 DM.Chronic oxidative stress,hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant,have high oxidative energy requirements,decrease the gene expression of key β-cell genes and induce cell death.If β-cell functioning is impaired,it results in an under production of insulin,impairs glucose stimulated insulin secretion,fasting hyperglycemia and eventually the development of T2 DM.     

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.     

Age related changes in pancreatic beta cells: A putativeextra-cerebral site of Alzheimer’s pathology

Frequent concomitant manifestation of type 2 diabetesmellitus (T2DM) and Alzheimer’s disease (AD) hasbeen recently demonstrated by epidemiological studies.This might be due to functional similarities between β-cells and neurons, such as secretion on demand ofhighly specific molecules in a tightly controlled fashion.An additional similarity represents the age-relatedalteration of hyperphosphorylated tau in AD patients.Similarly, alterations have been identified in β-cells of T2DM patients. The islet amyloid polypeptide has beenassociated with β-cell apoptosis. As a consequence ofincreasing age, the accumulation of highly modified proteins together with decreased regenerative potentialmight lead to increasing rates of apoptosis. Moreover, reduction of β-cell replication capabilities results in reduction of β-cell mass in mammals, simultaneously withimpaired glucose tolerance. The new challenge is tolearn much more about age-related protein modifications. This can lead to new treatment strategies forreducing the incidence of T2DM and AD.     

β-Cell Function,Incretin Effect,and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.     

Pharmacological control of blood sugar

Drugs that lower blood glucose are used to treat diabetes mellitus; this is the main clinical use of drugs affecting blood sugar. Type 1 diabetes is treated with insulin, of which the human sequence or its analogues are more commonly used than the bovine or porcine varieties. Insulin may also be use for non-insulin dependent diabetes (type 2) when oral hypoglycaemic drugs are inadequate to control the hyperglycaemia. These include the sulphonylureas (e.g. chlorpropamide, glibenclamide) and the meglinides (e.g. repaglinide, nateglinide), which stimulate insulin release. The biguanide metformin and the glitazones increase glucose uptake into tissue thus reducing insulin insensitivity. Alpha glucosidase inhibitors (e.g. acarbose) delay glucose absorption from the gut. Drugs that raise blood glucose include the natural hormone glucagon and the drug diazoxide; both of which are used to treat hypoglycaemia that occurs as a result of an insulinoma or excessive use of hypoglycaemic agents.     

Pharmacological control of blood sugar

Drugs that lower blood glucose are used to treat diabetes mellitus, the major clinical use of drugs affecting blood sugar. Type 1 diabetes is treated with insulin, of which the human sequence or analogues thereof are more commonly used than the bovine or porcine varieties. Insulin may also be used for non-insulin-dependent diabetes (type 2) when the oral hypoglycaemic drugs are inadequate to control the hyperglycaemia. These include the sulphonylureas, for example chlorpropamide, glibenclamide, and the meglitinides, for example repaglinide, nateglinide, which stimulate insulin release. The biguanide metformin and the glitazones increase glucose uptake into tissue thus reducing insulin insensitivity. α-Glucosidase inhibitors, for example acarbose, delay glucose absorption from the gut. Drugs that raise blood glucose include the natural hormone glucagon and the drug diazoxide; both of which are used to treat hypoglycaemia which occurs as a result of an insulinoma or excessive use of hypoglycaemic agents.     

The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes

In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.     

Global Biochemical Profiling Identifies β-Hydroxypyruvate as a Potential Mediator of Type 2 Diabetes in Mice and Humans

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the “incretin response.” To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin–expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. β-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting β-hydroxypyruvate production from d-serine. In vitro, β-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. β-Hydroxypyruvate–to–d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to β-hydroxypyruvate–to–d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and β-cells by regulating β-hydroxypyruvate levels.     

Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes

Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL^+/−) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell–specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell–specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis.     

慢性丙型肝炎合并2型糖尿病患者基因型特征分析

目的：了解慢性丙型肝炎并2型糖尿病患者基因型及相应的临床特征。方法检测88例慢性丙型肝炎并2型糖尿病患者与770例慢性丙型肝炎患者基因分型,分析88例慢性丙型肝炎并2型糖尿病患者的糖化血红蛋白、空腹血糖、空腹胰岛素、天门冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、γ-谷氨酰转肽酶（GGT）、总胆红素（TBil）、HCV RNA病毒载量及血甘油三酯等临床相关指标,并调查患者糖尿病确诊时间及抗病毒治疗情况。结果慢性丙型肝炎并2型糖尿病患者3a基因型占11.36%（10/88）,高于未合并2型糖尿病者3a基因型3.38%（26/770）,差异具有统计学意义（χ2=7.248,P=0.002）;并2型糖尿病的3a基因型患者的甘油三酯高于其他基因型（t=2.271,P =0.028）;糖尿病诊断时间多在抗病毒治疗前,部分患者控制血糖同时抗病毒治疗。结论感染丙型肝炎病毒3a基因型的患者更易并2型糖尿病,应监测血糖情况,尽早筛查糖尿病,早期诊治。     

Fatty liver disease in diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus (T2DM), likely reflecting the frequent occurrence of obesity and insulin resistance in T2DM. NAFLD also can occur in type 1 DM (T1DM), but must be distinguished from the more common glycogen hepatopathy as a cause of hepatomegaly and liver function abnormalities in T1DM. Weight reduction achieved by diet and exercise is effective in preventing and treating NAFLD in obese diabetic subjects. Bariatric surgery also has been shown to reverse NAFLD in T2DM, and recently approved weight loss medications should be evaluated for their impact on the development and progression of NAFLD. There is limited evidence suggesting that specific drugs used for blood glucose control in T2DM [thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors] and also statins may have a role in preventing or treating NAFLD in patients with diabetes.     

Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell-specific, 11β-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal-related kinase and p21 signaling pathways. 11β-HSD1(-/-) mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes.     

Laparoscopic Roux-en-Y gastric bypass for nonobese type II diabetes mellitus in Asian patients

BackgroundThe beneficial role of laparoscopic Roux-en-Y gastric bypass (LRYGB) for type 2 diabetes mellitus (T2 DM) in morbidly obese patients has been established; however, there is scant evidence supporting its effectiveness in nonobese T2 DM Asian patients. The objective of this study was to evaluate the effect of LRYGB in nonobese T2 DM patients and elucidate the predictors of DM remission after one year follow-up.MethodsBetween June 2009 and May 2011, twenty-nine nonobese (body mass index (BMI)<27 kg/m²) Asian patients with T2 DM who underwent LRYGB were enrolled. All patients were prospectively followed up for one year. Baseline demographic characteristics, diabetic status, and clinical and biochemical data were collected preoperatively and one year after LRYGB. DM remission was defined as those with hemoglobin A1 c (HbA1 c)<6.5% without oral hypoglycemic drugs (OHA)/insulin. Outcomes in the DM remission group were compared with the nonremission group and analyzed.ResultsAll clinical and biochemical parameters, except uric acid, were significantly improved. DM remission was achieved in eleven patients (37.9%) of whom five (45.5%) were male. Blood glucose, HbA1 c, c-peptide, homeostatic model assessment (HOMA-%B), and low density lipoprotein (LDL)-cholesterol were the significant variables in patients with DM remission; however, multiple logistic regression showed that only preoperative HOMA-%B (odds ratio (OR) = 1.13, 95% CI = 1.03-1.24) was a predictor for DM remission. Though no mortality was seen, the complication rate was 20.7%, of which 17.3% was related to marginal ulcers.ConclusionLRYGB resulted in significant clinical and biochemical improvements in nonobese Asian patients, with HOMA-%B indicating β-cell function as the main predictor of T2 DM remission. Appropriate patient selection with better β-cell function and evidence from long-term follow-up may justify this therapeutic approach.     

β-Cell Failure in Type 2 Diabetes: A Case of Asking Too Much of Too Few?

The islet in type 2 diabetes (T2DM) is characterized by a deficit in β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low β-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased β-cell workload results in T2DM in some but not all individuals. We propose that the extent of the β-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate β-cell mass in the face of subsequent insulin resistance may expose β-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising β-cell function and inducing β-cell apoptosis.