GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease?

To gain further insight into the mechanisms underlying muscle insulin resistance, the influence of obesity and type 2 diabetes on GLUT4 immunoreactivity in slow and fast skeletal muscle fibers was studied. Through a newly developed, very sensitive method using immunohistochemistry combined with morphometry, GLUT4 density was found to be significantly higher in slow compared with fast fibers in biopsy specimens from lean and obese subjects. In contrast, in type 2 diabetic subjects, GLUT4 density was significantly lower in slow compared with fast fibers. GLUT4 density in slow fibers from diabetic patients was reduced by 9% compared with the weight-matched obese subjects and by 18% compared with the lean control group. The slow-fiber fraction was reduced to 86% in the obese subjects and to 75% in the diabetic subjects compared with the control group. Estimated GLUT4 contribution from slow fibers was reduced to 77% in the obese subjects and to 61% in type 2 diabetic patients compared with the control subjects. We propose that a reduction in the fraction of slow-twitch fibers, combined with a reduction in GLUT4 expression in slow fibers, may reduce the insulin-sensitive GLUT4 pool in type 2 diabetes and thus contribute to skeletal muscle insulin resistance.     

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.     

Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study

BACKGROUND: The pathogenesis of diabetic nephropathy remains unclear, although previous reports implicate a wide range of putative genetic and metabolic factors. METHODS: Incident and prevalent cases of overt nephropathy (ON), defined as an albumin excretion rate>200 microg/min in at least two of the three timed urines, from the Pittsburgh Epidemiology of Diabetes Complication Study (a prospective epidemiologic study of an incident cohort of childhood onset type 1 diabetic subjects) were studied. RESULTS: Incidence analyses reveal differences in univariate baseline risk factors that predict ON within 5 years of measurement [low-density lipoprotein (LDL) cholesterol, triglycerides, white blood cell count, and hypertension] and those that predict in the long-term, that is, 6 to 10 years after baseline, hemoglobin A1 (Hb A1). Estimated glucose disposal rate (calculated using a formula derived from euglycemic-hyperinsulinemic clamp studies), however, strongly (P < 0.001) predicted ON throughout follow-up. Comparing individuals who were most susceptible to ON (those with an onset before 20 years duration of type 1 diabetes and before the development of other advanced complications) with the least susceptible (late or no occurrence of ON despite the development of other advanced complications) revealed otherwise undetected genetic associations [that is, apolipoprotein E (Apo E), angtiotensin-converting enzyme insertion/deletion (ACE I/D), and lipoprotein lipase (LPL) HindIII polymorphism) with odds ratios ranging from 2.9 to 7.1. CONCLUSIONS: In type 1 diabetes insulin resistance is an underlying risk state for ON, which may be accelerated by other disturbances (for example, hypertension and dyslipidemia). A novel approach to classifying (that is, phenotyping) subjects, which compares those at the extremes of susceptibility, reveals strong genetic associations and important interactions with other risk factors not otherwise apparent.     

Tanis: a link between type 2 diabetes and inflammation?

Here we describe a novel protein, which we have named Tanis, that is implicated in type 2 diabetes and inflammation. In Psammomys obesus, a unique polygenic animal model of type 2 diabetes and the metabolic syndrome, Tanis is expressed in the liver in inverse proportion to circulating glucose (P = 0.010) and insulin levels (P = 0.004) and in direct proportion with plasma triglyceride concentrations (P = 0.007). Hepatic Tanis gene expression was markedly increased (3.1-fold) after a 24-h fast in diabetic but not in nondiabetic P. obesus. In addition, glucose inhibited Tanis gene expression in cultured hepatocytes (P = 0.006) as well as in several other cell types (P = 0.001-0.011). Thus, Tanis seems to be regulated by glucose and is dysregulated in the diabetic state. Yeast-2 hybrid screening identified serum amyloid A (SAA), an acute-phase inflammatory response protein, as an interacting protein of Tanis, and this was confirmed by Biacore experiments. SAA and other acute-phase proteins have been the focus of recent attention as risk factors for cardiovascular disease, and we contend that Tanis and its interaction with SAA may provide a mechanistic link among type 2 diabetes, inflammation, and cardiovascular disease.     

Mouse models and the genetics of diabetes: is there evidence for genetic overlap between type 1 and type 2 diabetes?

In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic beta-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating beta-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to beta-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct.     

Cigarette smoking and risk of albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies

Background

The aim of this study was to assess the effects of smoking on albuminuria risk in adults with type 2 diabetes mellitus (T2DM).

Methods

A literature search was conducted using MEDLINE, EMBASE, and China National Knowledge Infrastructure from the established date to October 2017. Summary relative risks (SRR) and 95% confidence intervals (CI) were computed utilizing a random effect inverse variance method.

Results

This meta-analysis included a total of 19 relevant observational studies (four prospective cohort, seven case–control, and eight cross-sectional studies), reporting 105,031 participants and 23,366 albuminuria events. Compared with never-smokers with T2DM, the SRRs of albuminuria were 1.43 (95% CIs 1.27–1.61) for ever-smokers, 2.61 (95% CIs 1.86–3.64) for current smokers, and 1.86 (95% CIs 1.37–2.52) for former smokers. Considerable heterogeneity was observed among these studies, and study design was a significant modifier for this association. There were significantly elevated risk associations for microalbuminuria (SRRs = 1.24, 95% CIs 1.05–1.46) and for macroalbuminuria (SRRs = 1.65, 95% CIs 1.03–2.66), respectively.

Conclusions

Our systematic review and meta-analysis indicates that cigarette smoking might be a potential factor for the development of albuminuria in adults with T2DM. Future studies are required to investigate the association between smoking cessation and intensity and incident albuminuria in adults with T2DM.

     

Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1α expression and oxygen metabolism

OBJECTIVE

Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1α. We assess here the effects of the biguanide, metformin, on the expression of HIF-1α in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats.

RESEARCH DESIGN AND METHODS

We explored the effects of metformin on the expression of HIF-1α using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg ⋅ kg⁻¹ ⋅ day⁻¹) or insulin.

RESULTS

Metformin inhibited hypoxia-induced HIF-1α accumulation and the expression of HIF-1–targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP-activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1α expression. In addition, knockdown of AMPK-α did not abolish the inhibitory effects of metformin on HIF-1α expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1α accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1α expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1α expression and pimonidazole staining and ameliorated tubular injury in ZDF rats.

CONCLUSIONS

Our data suggest that hypoxia-induced HIF-1α accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption.Diabetic nephropathy now is a leading cause of end-stage renal failure and therefore constitutes a major component of progressive kidney disease. Chronic hypoxia and tubulointerstitial fibrosis presently are considered to be common pathways for various progressive kidney diseases, including diabetic nephropathy, and hypoxia-inducible factor (HIF)-1α plays an important role in these pathological mechanisms (1–4). Recent studies (4–6) have demonstrated that hypoxia represents an early event in the development and progression of diabetic nephropathy and an increase in HIF-1α expression in diabetic kidneys compared with the kidneys of control rats (7) and normal human kidneys (8). In addition, Higgins et al. (8) have demonstrated that HIF-1α enhanced the epithelial-to-mesenchymal transition (EMT) in vitro and that genetic ablation of renal epithelial HIF-1α inhibited the development of tubulointerstitial fibrosis using HIF-1α knockout mice. Sun et al. (9) further provided a novel explanation for the EMT of hypoxic renal tubular cells through the upregulation of Twist induced by HIF-1α. Kimura et al. (10) recently showed that stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis in knockout mice with von Hippel-Lindau (VHL) tumor suppressor, which acts as an ubiquitin ligase to promote proteolysis of HIF-α.Metformin has been widely used for treating type 2 diabetes without the stimulation of insulin production, and, for this reason, it is considered an insulin sensitizer (11). The UK Prospective Diabetes Study (UKPDS) showed that metformin could reduce macrovascular morbidity and mortality (12), suggesting that it achieved its antiatherogenic and anti-inflammatory effects by means of antioxidant properties (13). Moreover, metformin significantly decreased the urine albumin excretion rate in patients with type 2 diabetes (14). The benefits of metformin with regard to the risk of cardiovascular outcomes and metabolic parameters suggest its clinical use in treating chronic kidney disease (15). The precise mechanisms beyond the effects of metformin on glucose still are obscure. Recently, metformin has been found to activate AMP-activated protein kinase (AMPK), a major cellular regulator of lipid and glucose metabolism (16,17), via a liver kinase B1 (LKB1)-dependent mechanism (18). The LKB1-AMPK–mammalian target of rapamycin (mTOR) pathway is a key regulator of HIF-1–targeted genes and HIF-1–mediated cellular metabolism (19–21). In addition, a recent study (22) has shown that metformin inhibits insulin and IGF-1–induced HIF-1α expression in nontumor retinal epithelial ARPE-19 cells. This evidence led us to question whether metformin, known as an AMPK activator, might regulate the expression of HIF-1α protein in renal proximal tubular cells. Therefore, we investigated the effects of metformin on HIF-1α expression using cultured human renal proximal tubular epithelial cells (HRPTECs) and Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes (23).     

Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival?

OBJECTIVE: To compare the outcome of simultaneous pancreas-kidney transplantation (SPK) and living related donor renal transplantation (LRD) in patients with diabetes. SUMMARY BACKGROUND DATA: It remains unanswered whether diabetic patients with end-stage renal failure are better served by LRD or SPK. METHODS: Using a longitudinal database, data from all diabetic patients receiving LRD or cadaveric renal transplants or SPKs from January 1986 through January 1996 were analyzed. Patient and graft survival, early graft function, and the cause of patient and graft loss were compared for 43 HLA-identical LRDs, 87 haplotype-identical LRDs, 379 SPKs, and 296 cadaveric renal transplants. RESULTS: The demographic composition of the SPK and LRD groups were similar, but because of less strict selection criteria in the cadaveric transplant group, patients were 10 years older, more patients received dialysis, and patients had been receiving dialysis longer before transplantation. Patient survival was similar for the SPK and LRD groups but was significantly lower for the cadaveric renal transplant group. Similarly, there was no difference in graft survival between SPK and LRD recipients, but it was significantly lower for recipients in the cadaveric renal transplant group. Delayed graft function was significantly more common in the cadaveric renal transplant group. Discharge creatinine, the strongest predictor of patient and graft survival, was highest in the SPK group and lowest in the HLA-identical LRD group. The rate of rejection within the first year was greatest in SPK patients (77%), intermediate in the haplotype-identical LRD and cadaveric transplant groups (57% and 48%, respectively), and lowest (16%) in the HLA-identical LRD group. Cardiovascular disease was the primary cause of death for all groups. Acute rejection, chronic rejection, and death with a functioning graft were the predominant causes of graft loss. CONCLUSIONS: This study demonstrates that there was no difference in patient or graft survival in diabetic patients receiving LRD or SPK transplants. However, graft and patient survival rates in diabetic recipients of cadaveric renal transplants were significantly lower than in the other groups.     

Is there a role for bariatric surgery in patients with severe obesity and type 1 diabetes?

BackgroundThe prevalence of obesity in type 1 diabetes has been increasing over the past decades. Multiple studies have demonstrated suboptimal outcomes with dietary control and medical management for obesity and type 2 diabetes. This study’s objective was to evaluate insulin and diabetic medication requirements in patients with type 1 diabetes 2 years after bariatric surgery.MethodsThis was a retrospective medical-record review study from 2002 to 2019 at Geisinger Health System. Of 4549 total bariatric surgeries, 38 bariatric surgery patients were confirmed to have type 1 diabetes. Type 1 diabetes was confirmed by medical-record review and/or the presence of C-peptide <5 ng/mL.ResultsThe patient cohort had a mean age of 41 years, with 87% being female. The mean body mass index was 43.0 kg/m², with a mean HbA1C of 8.4% before surgery. During follow-up, the insulin requirements improved from 114 units preoperatively to 60 units at 1 year postoperatively (SD = 54.5, P = .0018) and 60 units at 2 years postoperatively (SD = 60.3, P = .0033). Though not significant, the number of patients on more than 1 diabetic medication decreased from 66% preoperatively to 53% 1 year postoperatively (P = .343) and 52% at 2 years (P = .149).ConclusionThis study demonstrated significant improvement in the insulin and total number of diabetic medication requirements after bariatric surgery, suggesting that bariatric surgery may be a viable treatment for patients with type 1 diabetes.     

Biochemical markers of bone turnover in diabetes patients—a meta-analysis,and a methodological study on the effects of glucose on bone markers

Summary

This study examined whether markers of bone turnover differ between individuals with and without diabetes. Bone markers showed heterogeneity between studies and were discrepant for markers of bone creation and markers of bone degradation. Bone markers may be of lesser value in diabetes due to heterogeneity.

Introduction

The aim of this meta-analysis was to compare existing literature regarding changes in bone markers among diabetics compared to healthy controls. To exclude that blood glucose levels among diabetes patients could influence the assays used for determining bone turnover markers, a methodological study was performed.

Methods

Medline at Pubmed Embase, Cinahl, Svemed+, Cochrane library, and Bibliotek.dk was searched in August 2012. The studies should examine biochemical bone turnover among diabetes patients in comparison to controls in an observational design. In the methodological study, fasting blood samples were drawn from two individuals. Glucose was added to the blood samples in different concentrations and OC, CTX, and procollagen type 1 amino terminal propeptide were measured after 0, 1, 2, and 3 h.

Results

Twenty-two papers fulfilled the criteria for the meta-analysis. From the pooled data in the meta-analysis, the bone markers osteocalcin (OC) (?1.15 ng/ml [?1.78,-0.52]) and C-terminal cross-linked telopeptide (CTX) (?0.14 ng/ml [?0.22, ?0.05]) were significantly lower among diabetes patients than non-diabetes patients, however other markers did not differ. All markers displayed very high heterogeneity by I2 statistics. In the methodological study, the addition of glucose did not significantly change the bone markers neither by level of glucose nor with increasing incubation time.

Conclusion

The dissociative pattern of biochemical bone markers of bone formation and bone resorption present in diabetes patients is thus not caused by glucose per se but may be modulated by unknown factors associated with diabetes mellitus.     

Is erectile dysfunction a sentinel symptom for cardiovascular autonomic neuropathy in patients with type 2 diabetes?

The study investigated whether there is a significant association between erectile dysfunction (ED) secondary to autonomic failure, and cardiovascular autonomic neuropathy (CAN) in male patients suffering from type 2 diabetes. Twenty-two patients suffering from type 2 diabetes were recruited for this study after satisfying the stringent exclusion criteria used in the first stage. They had no evidence of overt cardiovascular disease, hypertension, neurological, renal or thyroid disease. Each subject was assessed for ED and CAN using standardized tests. Six patients were suffering from CAN while 10 patients were suffering from ED. There was no significant association between CAN and autonomic ED (P = 1). Three patients with normal erectile function had CAN, whilst three patients with ED had CAN. Further analysis demonstrates a significant increase in association between ED and CAN with age (P = 0.036). These results show that ED secondary to autonomic neuropathy is not significantly associated with CAN in this specific group of patients. Nonetheless, the study reveals that ED is a sentinel symptom for future development of CAN.     

Type 1 and type 2 diabetes: what do they have in common?

Type 1 and type 2 diabetes frequently co-occur in the same families, suggesting common genetic susceptibility. Such mixed family history is associated with an intermediate phenotype of diabetes: insulin resistance and cardiovascular complications in type 1 diabetic patients and lower BMI and less cardiovascular complications as well as lower C-peptide concentrations in type 2 diabetic patients. GAD antibody positivity is more common in type 2 diabetic patients from mixed families than from common type 2 diabetes families. The mixed family history is associated with more type 1-like genetic (HLA and insulin gene) and phenotypic characteristics in type 2 diabetic patients, especially in the GAD antibody-positive subgroup. Leaving out the extreme ends of diabetes phenotypes, young children progressing rapidly to total insulin deficiency and strongly insulin-resistant subjects mostly with non-Europid ethnic origin, a large proportion of diabetic patients may have both type 1 and type 2 processes contributing to their diabetic phenotype.     

Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study

The objective of this is study was to examine whether estimated insulin resistance and insulin resistance-related factors are associated with coronary artery calcification (CAC) in 1,420 asymptomatic participants in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. A total of 656 patients with type 1 diabetes and 764 control subjects aged 20-55 years were examined. CAC was assessed by electron-beam computed tomography. Insulin resistance was computed with linear regression based on an equation previously validated in clamp studies on type 1 diabetic adults. Insulin resistance was associated with CAC (OR 1.6 in type 1 diabetes and 1.4 in control subjects, P < 0.001), independent of coronary artery disease risk factors. There was a male excess of CAC in control subjects (OR 2.7, adjusted for age, smoking, and LDL and HDL cholesterol levels) and in type 1 diabetic patients (OR 2.2, adjusted for the same factors and diabetes duration). After adjusting for insulin resistance, the CAC male excess in diabetic patients decreased from OR 2.2 (P < 0.001) to 1.8 (P = 0.04). After adjustment for waist-to-hip ratio, waist circumference, or visceral fat, the gender difference in CAC was not significant in diabetic subjects. In conclusion, gender differences in insulin resistance-associated fat distribution may explain why type 1 diabetes increases coronary calcification in women relatively more than in men.