Exogenous Insulin Therapy Research Articles

Skeletal muscle as a therapeutic target for delaying type 1 diabetic complications.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease targeting the pancreatic beta-cells and rendering the person hypoinsulinemic and hyperglycemic. Despite exogenous insulin therapy, individuals with T1DM will invariably develop long-term complications such as blindness, kidney failure and cardiovascular disease. Though often overlooked, skeletal muscle is also adversely affected in T1DM, with both physical and metabolic derangements reported. As the largest metabolic organ in the body, impairments to skeletal muscle health in T1DM would impact insulin sensitivity, glucose/lipid disposal and basal metabolic rate and thus affect the ability of persons with T1DM to manage their disease. In this review, we discuss the impact of T1DM on skeletal muscle health with a particular focus on the proposed mechanisms involved. We then identify and discuss established and potential adjuvant therapies which, in association with insulin therapy, would improve the health of skeletal muscle in those with T1DM and thereby improve disease management- ultimately delaying the onset and severity of other long-term diabetic complications.

Expanding the indications of pancreas transplantation alone.

Total pancreatectomy (TP) is associated with postoperative endocrine and exocrine insufficiency. Especially, insulin therapy reduces quality of life and may lead to long-term complications. We review the literature with regard to the potential option of pancreas transplantation alone (PTA) after TP in patients with chronic pancreatitis or benign tumors. A MEDLINE search (1958-2013) using the terminologies pancreas transplantation, pancreas transplantation alone, total pancreatectomy, morbidity, mortality, insulin therapy, and quality of life was performed. In addition, the current book and congress publications were reviewed. Total pancreatectomy after benign and borderline tumors as well as chronic pancreatitis is continuously increasing. Despite improvement of exogenous insulin therapy, more than 50% of these patients experience severe glucose control problems, which cause up to 50% long-term mortality. Pancreas transplantation alone can cure both endocrine and exocrine insufficiency and reduce the associated risks. The 3-year graft and patient survival rates after PTA are up to 73% and 100%, respectively. Pancreas transplantation alone after TP in patients with pancreatitis or benign tumors improves the recipient's quality of life and reduces long-term mortality. Considering the amount of available organs and potential candidates, PTA can be a treatment option for patients after TP with chronic pancreatitis or benign tumors.

Serum resistin concentrations in children with type 1 diabetes mellitus--negative relation to body fat mass.

Insulin is one of the major factors regulating adipose tissue function. On the other hand, adipocytes secrete adipocytokines that may influence insulin synthesis and action, and are involved in blood glucose regulation. In type 1 diabetes mellitus (t1DM), beta cells function is replaced with exogenous insulin therapy. This raises a question concerning the impact of t1DM on adipose tissue secretory function. The aim of this study was to evaluate one of the adipocytokines, resistin, serum concentrations in relation to body fat mass in children with t1DM. The study comprised 75 children with t1DM and a control group of 20 healthy coevals. All children had estimated serum resistin concentrations, glycated haemoglobin levels, growth and body weight measurements, and bioelectrical impedance analysis in order to establish body composition. Resistin serum concentrations were significantly lower in children with t1DM vs. controls (median values: 343 vs. 590 pg/mL; mean values ± SD: 577 ± 561 vs. 861 ± 628 pg/mL; p < 0.001), and they negatively correlated with body fat mass (p = 0.022) and age (p = 0.022) in the t1DM group, but not in the control group. Disease duration, glycated haemoglobin levels and insulin dosage revealed no direct statistical relation to resistin levels. Diminished serum resistin concentrations and a negative correlation between resistin levels and body fat mass in children with type 1 diabetes seem to result from broken physiological adipo-insular regulations, independent of disease duration, its metabolic control and insulin supply.

Recombinant canine single chain insulin analogues: Insulin receptor binding capacity and ability to stimulate glucose uptake

Virtually all diabetic dogs require exogenous insulin therapy to control their hyperglycaemia. In the UK, the only licensed insulin product currently available is a purified porcine insulin preparation. Recombinant insulin is somewhat problematic in terms of its manufacture, since the gene product (preproinsulin) undergoes substantial post-translational modification in pancreatic β cells before it becomes biologically active. The aim of the present study was to develop recombinant canine single chain insulin (SCI) analogues that could be produced in a prokaryotic expression system and which would require minimal processing. Three recombinant SCI constructs were developed in a prokaryotic expression vector, by replacing the insulin C-peptide sequence with one encoding a synthetic peptide (GGGPGKR), or with one of two insulin-like growth factor (IGF)-2 C-peptide coding sequences (human: SRVSRRSR; canine: SRVTRRSSR). Recombinant proteins were expressed in the periplasmic fraction of Escherichia coli and assessed for their ability to bind to the insulin and IGF-1 receptors, and to stimulate glucose uptake in 3T3-L1 adipocytes.All three recombinant SCI analogues demonstrated preferential binding to the insulin receptor compared to the IGF-1 receptor, with increased binding compared to recombinant canine proinsulin. The recombinant SCI analogues stimulated glucose uptake in 3T3-L1 adipocytes compared to negligible uptake using recombinant canine proinsulin, with the canine insulin/cIGF-2 chimaeric SCI analogue demonstrating the greatest effect. Thus, biologically-active recombinant canine SCI analogues can be produced relatively easily in bacteria, which could potentially be used for treatment of diabetic dogs.

Optimizing clinical outcomes resulting from glucose‐lowering therapies in type 2 diabetes: increased confidence about the DPP‐4 inhibitors and continued concerns regarding sulphonylureas and exogenous insulin

Optimizing clinical outcomes resulting from glucose‐lowering therapies in type 2 diabetes: increased confidence about the <scp>DPP</scp>‐4 inhibitors and continued concerns regarding sulphonylureas and exogenous insulin

Exogenous Insulin Therapy Is Associated With Increased Prostate Cancer Mortality in Men With Type 2 Diabetes Mellitus

Exogenous Insulin Therapy Is Associated With Increased Prostate Cancer Mortality in Men With Type 2 Diabetes Mellitus

What We Do and Donʼt Understand About Pancreas Graft Failure.

The purpose of this study was to analyze patterns of graft failure (GF) following pancreas transplantation (PT) in an attempt to develop a better understanding of GF. Methods: We retrospectively reviewed outcomes in 202 consecutive PTs in 192 patients at our center; all were insulin-requiring pretransplant and received either r-ATG or alemtuzumab induction with tacrolimus/mycophenolate ± steroids. GF was defined as a return to daily scheduled exogenous insulin therapy irrespective of dose. Results: From 11/01 to 3/13, we performed 162 simultaneous pancreas-kidney transplants (SPKT) and 40 solitary PTs. In the SPKT group, 51 patients had measurable pretransplant C-peptide levels. With a mean follow-up of 6 years, 76 (37.6%) pancreas GFs occurred including 20 deaths with functioning grafts (DWFG). The death-censored pancreas graft failure rate was 30.8%; of these 56 pancreas GFs, 20 occurred early (within 3 months of PT) and 36 occurred late. Rates of early thrombosis were 8% in SPKT and 5% in solitary PT patients. Death-censored causes of pancreas GF were acute/chronic rejection (34), thrombosis (18), infection (3) and one primary nonfunction. Allograft pancreatectomy (AP) was performed in 22 cases; rates of AP were 95% for early (<3 months) and 11.8% for late pancreas GF (p<0.001). After excluding DWFGs and pancreas GFs that resulted in AP, a total of 36 pancreas GFs remained, 10 of which did not have C-peptide data at the time of pancreas GF. Of the remaining 26 pancreas GFs, 13 occurred in patients who were C-peptide positive (mean pretransplant C-peptide level 5.7 ng/ml). In these 13 cases, the mean C-peptide level at the time of pancreas GF (insulin resumption) was 3.3 ng/ml (range 0.9-7.9). In all but one case, the C-peptide level at the time of pancreas GF was less than the pretransplant C-peptide level. Of 13 pancreas GFs in pretransplant C-peptide negative patients, the mean C-peptide level at the time of pancreas GF was 1.5 ng/ml (range 0-3.8); 5 had C-peptide levels ≥2.0, 4 had C-peptide levels 1-2, and 4 had C-peptide levels <1.0 ng/ml. Conclusions: DWFG and AP account for more than half of cases of pancreas GF. Of the remaining cases of GF (defined as loss of insulin independence), C-peptide levels appear to be of limited predictive value whether or not the patient had detectable C-peptide levels pretransplant.

Recurrent Hypoglycemia Following Total Pancreatectomy and Islet Autotransplantation.

Total pancreatectomy and Islet autotransplantation (TP-IAT) is a treatment modality for chronic pancreatitis after therapies have been exhausted. The aim to prevent surgical diabetes in these patients is achieved in approximately one third of cases. In another third, autograft function is insufficient to achieve insulin independence while still improving glucose management. We report a case of an insulin independent islet autograft recipient, experiencing frequent hypoglycemia. The patient developed symptoms of abdominal pain her early thirties, leading to the diagnosis of idiopathic pancreatitis and subsequent Whipple resection of the pancreatic head in 2003 followed by a symptom free interval. Obstruction of the pancreaticojejunostomy necessitated a surgical revision and Roux-en-Y reconstruction of the gastrojeujunostomy in 2008. An episode of acute on chronic pancreatitis and recurring symptoms culminated in the indication of completion pancreatectomy and splenectomy, followed by IAT in 2012. The islet Isolation from the pancreas remnant (29 g) yielded a total Islet equivalents (IEQ) of 267,000 (5650,000 IEQ/kg BW). Islets were infused into the liver via the splenic vein stump under systemic heparinization. Post-operative blood glucose (BG) levels did not exceed 160 mg/dl. Following the discontinuation of protective exogenous insulin therapy 3 months postoperatively, the patient experienced hypoglycemia with increasing frequency and intensity, especially postprandial, following physical exercise and at night. Supportive treatment with a diet of Carbohydrates with low Glycemic index and Acarbose were initiated but failed to prevent hypoglycemia. Extensive workup and metabolic testing revealed a relative lack of glucagon response to hypoglycemia, reduced first phase insulin secretion, impaired Cortisol response to hypoglycemia and impaired postprandial incretin release. In conclusion, we report the rare case of Hypoglycemia complicating the outcome of IAT. Mechanisms of post IAT hypoglycemia remain elusive despite some evidence for impaired Glucagon action. Treatment thus far is limited to glycemic management with continuous glucose monitoring and therapeutic glucose intake.

Transplantation of betacellulin-transduced islets improves glucose intolerance in diabetic mice.

Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic β cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes β-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.

Evaluation of the Effectiveness and Safety of Basal Based Therapy with Insulin Glargine and Prandial Insulin in Patients with Type 2 Diabetes Poorly Controlled with Premixed Insulin

Abstract Introduction. Type 2 diabetes mellitus (T2DM) is a progressive disease, requiring treatment intensification and exogenous insulin therapy in many patients. The aim of the study was to evaluate the effectiveness and safety of insulin glargine in combination with prandial insulin in poorly controlled type 2 patients previously treated with premixed insulin. Methods. A total of 200 type 2 diabetic patients in Macedonia (male 37.5%; female 62.5%, aged 61.1±0.5 years) poorly controlled (HbA1c&gt;7%) were included in this observational multicenter prospective study. Before enrolment, all patients were treated with premixed insulin (88% with 2 and 12% with 3 injections per day, respectively). During the study, patients received once-daily glargine plus pre-prandial short-acting insulin analogues at investigators’ discretion. Primary end-point included percentage of patients achieving HbA1c &lt;7% at study end. In addition, changes in mean HbA1c and fasting plasma glucose (FPG) during the study duration as well as frequency of hypoglycaemic episodes were evaluated. Results. After 9 months of follow-up, 100 patients (50%) achieved target HbA1c &lt;7%. Mean HbA1c decreased from 9.5±1.5% at the beginning to 6.9±0.8% (p&lt;0.001) at study end and mean FPG decreased from 11.0±3.3 mmol/l to 6.1± 0.9 mmol/l (p&lt;0.001). 50.5% of the patients were treated with basal insulin in combination with OADs and 49.5% required addition of one or more prandial insulin injections. No episodes of severe hypoglycaemia were documented. Conclusions. Basal based insulin treatment with insulin glargine alone or in combination with prandial insulin improved glycaemic control in type 2 diabetics previously poorly controlled with premixed insulin with a low risk of hypoglycaemia and weight gain.

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long-term hypoglycemia or reduce diabetes-related complications.

Anti-inflammatory Interventional Strategies to Promote Islet Transplantation Outcomes

While exogenous insulin therapy remains the most common and effective standard for day-to-day control of Type 1 Diabetes (T1D), recurring incidences of hypoglycemic episodes and long-term complications such as retinopathy, neuropathy, nephropathy, and cerebrovascular/cardiovascular diseases necessitate transplantation of either whole pancreas or pancreatic islets as a more effective treatment in a high percentage of patients [1-6]. Of the two, clinical islet transplantation is less invasive, being associated with a 20% lower morbidity risk compared to whole pancreas transplantation. At the same time, it offers substantial benefits in terms of lowering daily insulin requirement, improving levels of glycated hemoglobin (HbA1c), reducing incidences of debilitating hypoglycemic episodes and unawareness, and affording potential insulin independence. However, widespread applicability of the procedure is mainly hindered by an inadequate supply of donor pancreata, graft rejection, recurrence of autoimmunity, deleterious side-effects associated with chronic immune-suppression, and last but not least, financial considerations [1].

Characterization of Insulin Antibodies by Surface Plasmon Resonance in Two Clinical Cases: Brittle Diabetes and Insulin Autoimmune Syndrome

In this study, the characterization of insulin (auto)antibodies has been described, mainly in terms of concentration (q), affinity (Ka) and Ig (sub)isotypes by Surface Plasmon Resonance (SPR) in two particular clinical cases of individuals with severe episodes of impaired glycemia. Subject 1 suffers from brittle diabetes associated with circulating insulin antibodies (IA) due to insulin treatment. Subject 2 has insulin autoantibodies (IAA) associated with hypoglycemia in spite of not being diabetic and not having ever received exogenous insulin therapy. After conventional screening for IA/IAA by radioligand binding assay (RBA), we further characterized IA/IAA in sera of both patients in terms of concentration (q), affinity (Ka) and Ig (sub)isotypes by means of SPR technology. In both cases, q values were higher and Ka values were lower than those obtained in type 1 diabetic patients, suggesting that IA/IAA:insulin immunocomplexes could be responsible for the uncontrolled glycemia. Moreover, subject 1 had a predominat IgG1 response and subject 2 had an IgG3 response. In conclusion, SPR technology is useful for the complete characterization of IA/IAA which can be used in special cases where the simple positive/negative determination is not enough to achieve a detailed description of the disease fisiopathology.

Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies

Objective:An increasing number of studies show that exogenous insulin therapy may promote colorectal carcinogenesis. However, the results of the association between insulin therapy and risk of colorectal cancer (CRC) among type 2 diabetes patients are inconsistent. The purpose of our study is to examine the effect of insulin therapy on CRC risk among patients with type 2 diabetes in an updated meta-analysis.Research design and methods:Medline and Embase were searched for the reference lists of pertinent articles published from January 1970 to April 2013. Two investigators independently extracted the data and reached consensus on the inclusion and exclusion criteria. Pooled relative risks and 95% confidence intervals were calculated with a random-effects model.Results:Analysis of six studies, including 374,950 participants, showed that compared with non-insulin or metformin treatment, insulin treatment was associated with an increase of 37% in the risk of colorectal neoplasm among patients with type 2 diabetes, with moderate heterogeneity (I 2 = 40%). The sensitivity analysis showed that exclusion of one small case–control study had no appreciable changes on the pooled results. Subgroup analyses suggested that there were significant positive associations between insulin therapy and risk of CRC in some subgroups, rather than all subgroups.Conclusions:Our meta-analysis supports a relationship between insulin therapy and increased risk of CRC in patients with type 2 diabetes. Because of bias and confounding of included studies, caution is needed when interpreting our results. Further investigations are needed.

Insulin Pump for Type 2 Diabetes

Progressive hyperglycemia in type 2 diabetes results from a progressive β-cell failure together with a state of insulin resistance (1). Insulin deficiency worsens with the natural progression of type 2 diabetes, explaining the escape from oral antihyperglycemic agents and the need for exogenous insulin therapy (2). The use of external pumps in patients with type 2 diabetes is a recent practice compared with that in type 1 diabetes, and its use is still debated. In only a few countries, such as in France and Israel, continuous subcutaneous insulin infusion (CSII) using an external pump is an alternative in type 2 diabetes that the health authorities have allowed for reimbursement. The rationale for using pump therapy was first suggested by its use in case reports of type 2 diabetes with extreme insulin resistance and poor glycemic control (3–6). In such patients, insulin was administered transiently by intravenous insulin infusion allowing lower mean glucose level despite a 40% reduction of insulin requirements. The sequential use of 4-week intravenous insulin infusion followed by 1-year CSII in a group of patients with type 2 diabetes patients poorly controlled despite very high insulin requirements allowed a dramatic reduction of HbA1c (−3%, −9 mmol/mol), while insulin requirements were reduced by one-third. Such beneficial effects of CSII were attributed to increased insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp study (7). These observations raised the question as to whether insulin continuous administration by a pump device gives an advantage compared with the conventional approach of insulin intensification by multiple daily injections (MDIs). The evidence base is still under debate and will be discussed in this review. ### Is CSII effective for the intensification of insulin therapy in type 2 diabetes? Very few randomized controlled studies have looked at the comparative effectiveness of CSII versus MDI (8–11) (Table 1). Two parallel-group studies performed over 6 and 12 …

Prevention versus intervention of type 1 diabetes

Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials.

Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes

Type 1 diabetes (T1DM) affects one in every 400 children and adolescents in the US. Due to the limitations of exogenous insulin therapy and whole pancreas transplantation, pancreatic islet transplantation has emerged as a promising therapy for T1DM. However, this therapy is severely limited by donor islet availability and poor islet engraftment and function. We engineered an injectable bio-synthetic, polyethylene glycol-maleimide hydrogel to enhance vascularization and engraftment of transplanted pancreatic islets in a mouse model of T1DM. Controlled presentation of VEGF-A and cell-adhesive peptides within this engineered material significantly improved the vascularization and function of islets delivered to the small bowel mesentery, a metabolically relevant site for insulin release. Diabetic mice receiving islets transplanted in proteolytically degradable hydrogels incorporating VEGF-A exhibited complete reversal of diabetic hyperglycemia with a 40% reduction in the number of islets required. Furthermore, hydrogel-delivered islets significantly improved weight gain, regulation of a glucose challenge, and intra-islet vascularization and engraftment compared to the clinical standard of islet infusion through the hepatic portal vein. This study establishes a simple biomaterial strategy for islet transplantation to promote enhanced islet engraftment and function.

A model of poorly controlled type 1 diabetes mellitus and its treatment with aerobic exercise training

BackgroundModern exogenous insulin therapy can improve the quality of life of Type 1 Diabetic Mellitus (T1DM) patients, although maintenance of normal glycaemic levels is often a challenge given the variety of factors that alter it. A number of studies have examined the effect of exercise in T1DM; however, the majority of experimental studies have utilized diabetic rodents with severe hyperglycaemia. Given that T1DM patients are likely to refrain from hyperglycaemia, studies examining the effects of regular exercise in which blood glucose is poorly controlled would better represent the T1DM population. MethodsThe current study examined the ability of a ten-week aerobic exercise training program to modify markers of cardiovascular function and bone health in STZ-induced diabetic rodents maintained in the 9–15mM glycaemic range through insulin therapy. ResultsModerate hyperglycaemia, when prolonged, leads to significant changes in cardiac structure, bone health, and glucose handling capacity. Ten weeks of exercise was able to alleviate many of these deleterious events as no significant cardiovascular functional alterations were evident except a reduction in resting heart rate and an increase in stroke volume index. Further, despite changes in cardiac dimensions, exercise was able to elevate cardiac output index and increase the E/A ratio of exercising diabetic animals which would be indicative of improvements of cardiac function. ConclusionsTogether, this study demonstrates that despite moderate hyperglycaemia, the combined role of a ten-week exercise training program coupled with insulin therapy is able to alleviate many of the well-known complications associated with diabetes progression.

Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Therapies in Type 2 Diabetes

Context:The safety of insulin in the treatment of type 2 diabetes mellitus (T2DM) has recently undergone scrutiny.Objective:The objective of the study was to characterize the risk of adverse events associated with glucose-lowering therapies in people with T2DM.Design and Setting:This was a retrospective cohort study using data from the UK General Practice Research Database, 2000–2010.Patients:Patients comprised 84 622 primary care patients with T2DM treated with one of five glucose-lowering regimens: metformin monotherapy, sulfonylurea monotherapy, insulin monotherapy, metformin plus sulfonylurea combination therapy, and insulin plus metformin combination therapy. There were 105 123 exposure periods.Main Outcome Measures:The risk of the first major adverse cardiac event, first cancer, or mortality was measured. Secondary outcomes included these individual constituents and microvascular complications.Results:In the same model, and using metformin monotherapy as the referent, the adjusted hazard ratio (aHR) for the primary end point was significantly increased for sulfonylurea monotherapy (1.436, 95% confidence interval [CI] 1.354–1.523), insulin monotherapy (1.808, 95% CI 1.630–2.005), and insulin plus metformin (1.309, 95% CI 1.150–1.491). In glycosylated hemoglobin/morbidity subgroups, patients treated with insulin monotherapy had aHRs for the primary outcome ranging from 1.469 (95% CI 0.978–2.206) to 2.644 (95% CI 1.896–3.687). For all secondary outcomes, insulin monotherapy had increased aHRs: myocardial infarction (1.954, 95% CI 1.479–2.583), major adverse cardiac events (1.736, 95% CI 1.441–2.092), stroke (1.432, 95% CI 1.159–1.771), renal complications (3.504, 95% CI 2.718–4.518), neuropathy (2.146, 95% CI 1.832–2.514), eye complications (1.171, 95% CI 1.057–1.298), cancer (1.437, 95% CI 1.234–1.674), or all-cause mortality (2.197, 95% CI 1.983–2.434). When compared directly, aHRs were higher for insulin monotherapy vs all other regimens for the primary end point and all-cause mortality.Conclusions:In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality. Differences in baseline characteristics between treatment groups should be considered when interpreting these results.

Hyperglycaemia is associated with impaired pulsatile insulin secretion: effect of basal insulin therapy

Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031). Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous β-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.