A novel insulin sensitivity index particularly suitable to measure insulin sensitivity during gestation

Aims

Insulin resistance underlies the etiology of both type 2 diabetes and gestational diabetes. In pregnancy, insulin resistance is also associated with an unfavorable metabolic programming of the fetus, potentially contributing to a higher risk of obesity and type 2 diabetes in the offspring. To assess insulin sensitivity, several methods based on glucose and insulin levels during a 75-g oral glucose tolerance test (OGTT) exist. It is unclear how they perform during pregnancy, where physiologically altered metabolism could introduce a bias.

Methods

In a cohort comprising 476 non-diabetic subjects undergoing OGTT and hyperinsulinemic-euglycemic clamp (HEC), we used cross-validation to develop an insulin sensitivity index also based on non-esterified fatty acids (NEFA) that could be more robust during pregnancy (NEFA-index). We tested commonly used OGTT-based indexes and the NEFA-index in a different cohort of 42 women during pregnancy and 1 year after delivery.

Results

The Matsuda and OGIS index failed to detect lower insulin sensitivity during pregnancy as compared to the follow-up OGTT 1 year after delivery (p > 0.09). The new NEFA-index incorporating BMI, plasma insulin and NEFA, but not glucose, clearly indicated lower insulin sensitivity during pregnancy (p < 0.0001). In the non-pregnant cohort, this NEFA-index correlated well with the gold-standard HEC-based insulin sensitivity index, and outperformed other tested indexes for the prediction of HEC-measured insulin resistance.

Conclusions

This insulin/NEFA-based approach is feasible, robust, and could be consistently used to estimate insulin sensitivity also during pregnancy.

     

Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study

Aims/hypothesis

Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention.

Methods

Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 ± 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0–120 min during OGTT (AUCglucose_0–120 min).

Results

Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control.

Conclusions/interpretation

Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the confirmed factors, impaired insulin secretion and insulin sensitivity.

     

Hepatogener Diabetes

Background

Disturbances of glucose metabolism are common in chronic liver disease and about 30–40?% of patients with liver cirrhosis develop type 2 diabetes. The diabetes may be a direct consequence of the hepatic disease due to excessive insulin resistance or may be caused by classical type 2 diabetes.

Blood glucose determination

Patients with chronic liver disease frequently have a normal fasting glucose despite manifest type 2 diabetes with postprandial excessive increases in glucose. Therefore, oral glucose tolerance tests should be performed after diagnosis of hepatic cirrhosis.

Prognosis

Diabetes mellitus is associated with increased mortality and an increased risk of complications of liver cirrhosis including premature death, hepatocellular carcinoma, hepatic encephalopathy, and spontaneous bacterial peritonitis. Therapy of diabetes should include metformin and α?glucosidase inhibitors which can reduce the risk of these complications. Therefore, the diagnosis of diabetes has important consequences in chronic liver disease.

     

Critical Care Management of Stress-Induced Hyperglycemia

Purpose of Review

We discuss key studies that have set the scene for the debate on the efficacy and safety of tight glycemic control in critically ill patients, highlighting important differences among them, and describe the ensuing search towards strategies for safer glucose control.

Recent Findings

Differences in level of glycemic control, glucose measurement and insulin administration, expertise, and nutritional management may explain the divergent outcomes of the landmark studies on tight glycemic control in critical illness. Regarding strategies towards safer glucose control, several computerized algorithms have shown promise, but lack validation in adequately powered outcome studies. Real-time continuous glucose monitoring and closed loop blood glucose control systems are not up to the task yet due to technical challenges, though recent advances are promising. Alternatives for insulin have only been investigated in small feasibility studies.

Summary

Severe hyperglycemia in critically ill patients generally is not tolerated anymore, but the optimal blood glucose target may depend on the specific patient and logistic context.

     

Altered glucose profiles and risk for hypoglycaemia during oral glucose tolerance testing in pregnancies after gastric bypass surgery

Aims/hypothesis

A history of gastric bypass surgery can influence the results of the OGTT recommended during pregnancy. Therefore, we compared OGTT glucose kinetics and pregnancy outcome between pregnant gastric bypass patients and BMI-matched, lean and obese controls.

Methods

Medical records were used to collect data on glucose measurements during the 2 h 75 g OGTT as well as on pregnancy and fetal outcome for 304 women (n?=?76 per group, matched for age and date of delivery).

Results

Women after bariatric surgery had lower fasting glucose levels compared with lean, obese and BMI-matched controls, and showed altered postprandial glucose kinetics, including a rise at 60 min followed by hypoglycaemia with serum glucose of <3.34 mmol/l (which occurred in 54.8%). Moreover, their risk of pre-eclampsia or gestational hypertension was reduced, with an increased risk of delivering small for gestational age infants.

Conclusions/interpretation

Alternative strategies to accurately define impaired glucose metabolism in pregnancies after bariatric surgery should be explored.

     

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes

Aims/hypothesis

Incretin effect—the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route—is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans.

Methods

Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3 h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (P_GLU) and incretin-induced potentiation (P_INCR); the oral glucose sensitivity index was used to estimate insulin sensitivity.

Results

Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m² on OGTT and from 29 nmol/m² [26] to 57 nmol/m² [30] on ISO) and induced insulin resistance. P_INCR decreased from 1.6 [1.1] to 1.3 [0.1] (p?<?0.05). β-GS, P_GLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, P_INCR, P_GLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes.

Conclusions/interpretation

Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.

     

Predictors of Insulin Initiation in Patients with Type 2 Diabetes: An Analysis of the Look AHEAD Randomized Trial

Background

The decision to initiate insulin in patients with type 2 diabetes is a challenging escalation of care that requires an individualized approach. However, the sociodemographic and clinical factors affecting insulin initiation are not well understood.

Objective

We sought to identify patient factors that were independent predictors of insulin initiation among participants in the Look AHEAD (Action for Health in Diabetes) clinical trial.

Design

Retrospective analysis of a randomized clinical trial.

Participants

Beginning in 2001, Look AHEAD enrolled ambulatory U.S. adults with type 2 diabetes who were overweight or obese and had a primary healthcare provider. Participants were randomized (1:1) to an intensive lifestyle intervention, or diabetes support and education. This study examined 3913 participants across the two trial arms who were not using insulin at baseline.

Main Measures

We used Cox proportional hazards models to estimate the association between participant characteristics and time to insulin initiation. We performed time-varying adjustment for HbA1c measured eight times over the 10-year study period, as well as for multiple clinical and socioeconomic factors.

Key Results

A total of 1087 participants (27.8%) initiated insulin during a median follow-up of 8.0 years. Age was inversely associated with insulin initiation (adjusted hazard ratio [aHR] 0.88 per 10 years, P?=?0.025). The risk of insulin initiation was greater with a higher number of diabetes complications (P?<?0.001 for trend); chronic kidney disease and cardiovascular disease were independently associated with insulin initiation. There was a lower risk of insulin initiation in black (aHR 0.77, P?=?0.008) and Hispanic participants (aHR 0.66, P?<?0.001) relative to white participants. Socioeconomic factors were not associated with insulin initiation.

Conclusions

Patient age, race/ethnicity, and diabetes complications may influence insulin initiation in type 2 diabetes, independent of glycemic control. Future work is needed to understand the drivers of racial differences in antihyperglycemic treatment, and to identify patients who benefit most from insulin.

     

Fat Versus Carbohydrate-Based Energy-Restricted Diets for Weight Loss in Patients With Type 2 Diabetes

Purpose of Review

The prevalence of combined obesity and diabetes has increased dramatically in the last few decades. Although medical and surgical weight management are variably effective in addressing this epidemic, it is essential to parallel these strategies with a hypocaloric diet comprising the appropriate macronutrient composition to induce weight loss, enhance glycemic control, and improve cardiovascular risk factors. This review reports the current evidence of the role of carbohydrates and fat-based diets for weight management in patients with combined type 2 diabetes (T2D) and obesity.

Recent Findings

Low-carbohydrate diets were shown to decrease postprandial glucose levels whereas high-carbohydrate, low-fat diets are considered cardio-protective.

Summary

A diet with an optimal macronutrient composition remains uncertain for patients with combined T2D and obesity. Further research is still needed to define the best dietary composition that achieves the maximum benefits on weight management, glycemic control, and cardiovascular risk factors.

     

Kardiovaskuläre Effekte der Insulintherapie

Background

The importance of a near normal blood glucose adjustment and insulin therapy for prevention of subsequent microangiopathic diseases is undisputed.

Type 1 diabetes

The important role of intensive insulin therapy for prevention of cardiovascular events in type 1 diabetes has been clearly confirmed by the diabetes control and complications trial (DCCT) of the epidemiology of diabetes interventions and complications (EDIC) research group: in the long term, intensive insulin therapy reduces the risk of non-fatal myocardial infarction, stroke and death from cardiovascular causes by 57?%.

Type 2 diabetes

For patients with type 2 diabetes a cardiovascular benefit of early insulin therapy with near normal blood glucose adjustment was confirmed by the United Kingdom prospective diabetes study (UKPDS) but only becomes apparent in the follow-up period. In insulin therapy of long-standing diabetes mellitus and/or pre-existing cardiovascular diseases, priority is given to avoidance of hypoglycemia in order to prevent acute cardiovascular events. For patients with heart insufficiency the indications are that high insulin dosages should be avoided where possible and the benefit of a near normal blood glucose adjustment has also not been proven.

     

Emerging Technologies for the Management of Type 1 Diabetes in Pregnancy

Purpose of Review

The purpose of the study is to discuss emerging technologies available in the management of type 1 diabetes in pregnancy.

Recent Findings

The latest evidence suggests that continuous glucose monitoring (CGM) should be offered to all women on intensive insulin therapy in early pregnancy. Studies have additionally demonstrated the ability of CGM to help gain insight into specific glucose profiles as they relate to glycaemic targets and pregnancy outcomes. Despite new studies comparing insulin pump therapy to multiple daily injections, its effectiveness in improving glucose and pregnancy outcomes remains unclear. Sensor-integrated insulin delivery (also called artificial pancreas or closed-loop insulin delivery) in pregnancy has been demonstrated to improve time in target and performs well despite the changing insulin demands of pregnancy.

Summary

Emerging technologies show promise in the management of type 1 diabetes in pregnancy; however, research must continue to keep up as technology advances. Further research is needed to clarify the role technology can play in optimising glucose control before and during pregnancy as well as to understand which women are candidates for sensor-integrated insulin delivery.

     

Glucose patterns during an oral glucose tolerance test and associations with future diabetes,cardiovascular disease and all-cause mortality rate

Aims/hypothesis

In addition to blood glucose concentrations measured in the fasting state and 2 h after an OGTT, intermediate measures during an OGTT may provide additional information regarding a person’s risk of future diabetes and cardiovascular disease (CVD). First, we aimed to characterise heterogeneity of glycaemic patterns based on three time points during an OGTT. Second, we compared the incidences of diabetes and CVD and all-cause mortality rates among those with different patterns.

Methods

Our cohort study included 5861 participants without diabetes at baseline from the Danish Inter99 study. At baseline, all participants underwent an OGTT with measurements of plasma glucose levels at 0, 30 and 120 min. Latent class mixed-effects models were fitted to identify distinct patterns of glycaemic response during the OGTT. Information regarding incident diabetes, CVD and all-cause mortality rates during a median follow-up time of 11, 12 and 13 years, respectively, was extracted from national registers. Cox proportional hazard models with adjustment for several cardiometabolic risk factors were used to compare the risk of diabetes, CVD and all-cause mortality among individuals in the different latent classes.

Results

Four distinct glucose patterns during the OGTT were identified. One pattern was characterised by high 30 min but low 2 h glucose values. Participants with this pattern had an increased risk of developing diabetes compared with participants with lower 30 min and 2 h glucose levels (HR 4.1 [95% CI 2.2, 7.6]) and participants with higher 2 h but lower 30 min glucose levels (HR 1.5 [95% CI 1.0, 2.2]). Furthermore, the all-cause mortality rate differed between the groups with significantly higher rates in the two groups with elevated 30 min glucose. Only small non-significant differences in risk of future CVD were observed across latent classes after confounder adjustment.

Conclusions/interpretation

Elevated 30 min glucose is associated with increased risk of diabetes and all-cause mortality rate independent of fasting and 2 h glucose levels. Therefore, subgroups at high risk may not be revealed when considering only fasting and 2 h glucose levels during an OGTT.

     

Fasting and oral glucose-stimulated levels of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are highly familial traits

Aims/hypothesis

Heritability estimates have shown a varying degree of genetic contribution to traits related to type 2 diabetes. Therefore, the objective of this study was to investigate the familiality of fasting and stimulated measures of plasma glucose, serum insulin, serum C-peptide, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) among non-diabetic relatives of Danish type 2 diabetic patients.

Methods

Sixty-one families comprising 193 non-diabetic offspring, 29 non-diabetic spouses, 72 non-diabetic relatives (parent, sibling, etc.) and two non-related relatives underwent a 4 h 75 g OGTT with measurements of plasma glucose, serum insulin, serum C-peptide, plasma GIP and plasma GLP-1 levels at 18 time points. Insulin secretion rates (ISR) and beta cell responses to glucose, GIP and GLP-1 were calculated. Familiality was estimated based on OGTT-derived measures.

Results

A high level of familiality was observed during the OGTT for plasma levels of GIP and GLP-1, with peak familiality values of 74?±?16% and 65?±?15%, respectively (h ²?±?SE). Familiality values were lower for plasma glucose, serum insulin and serum C-peptide during the OGTT (range 8–48%, 14–44% and 15–61%, respectively). ISR presented the highest familiality value at fasting reaching 59?±?16%. Beta cell responsiveness to glucose, GLP-1 and GIP also revealed a strong genetic influence, with peak familiality estimates of 62?±?13%, 76?±?15% and 70?±?14%, respectively.

Conclusions/interpretation

Our results suggest that circulating levels of GIP and GLP-1 as well as beta cell response to these incretins are highly familial compared with more commonly investigated measures of glucose homeostasis such as fasting and stimulated plasma glucose, serum insulin and serum C-peptide.

     

Artificial Pancreas or Novel Beta-Cell Replacement Therapies: a Race for Optimal Glycemic Control?

Purpose of Review

New treatment strategies are needed for patients with type 1 diabetes (T1D). Closed loop insulin delivery and beta-cell replacement therapy are promising new strategies. This review aims to give an insight in the most relevant literature on this topic and to compare the two radically different treatment modalities.

Recent Findings

Multiple clinical studies have been performed with closed loop insulin delivery devices and have shown an improvement in overall glycemic control and time spent in hypoglycemia. Beta-cell transplantation has been shown to normalize or greatly improve glycemic control in T1D, but the donor organ shortage and the necessity to use immunosuppressive agents are major drawbacks. Donor organ shortage may be solved by the utilization of stem cell-derived beta cells, which has shown great promise in animal models and are now tested in clinical studies. Immunosuppression may be avoided by encapsulation.

Summary

Closed loop insulin delivery devices are promising treatment strategies and are likely to be used in clinical practice in the short term. But this approach will always suffer from delays in glucose measurement and insulin action preventing it from normalizing glycemic control. In the long term, stem cell-derived beta cell transplantation may be able to achieve this, but wide implementation in clinical practice is still far away.

     

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia

Aims/hypothesis

Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1).

Methods

We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs).

Results

Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion.

Conclusions/interpretation

GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy.

Trial registration:

ClinicalTrials.gov NCT02550145

     

Prediction of clamp-derived insulin sensitivity from the oral glucose insulin sensitivity index

Aims/hypothesis

The euglycaemic–hyperinsulinaemic clamp is the gold-standard method for measuring insulin sensitivity, but is less suitable for large clinical trials. Thus, several indices have been developed for evaluating insulin sensitivity from the oral glucose tolerance test (OGTT). However, most of them yield values different from those obtained by the clamp method. The aim of this study was to develop a new index to predict clamp-derived insulin sensitivity (M value) from the OGTT-derived oral glucose insulin sensitivity index (OGIS).

Methods

We analysed datasets of people that underwent both a clamp and an OGTT or meal test, thereby allowing calculation of both the M value and OGIS. The population was divided into a training and a validation cohort (n?=?359 and n?=?154, respectively). After a stepwise selection approach, the best model for M value prediction was applied to the validation cohort. This cohort was also divided into subgroups according to glucose tolerance, obesity category and age.

Results

The new index, called PREDIcted M (PREDIM), was based on OGIS, BMI, 2 h glucose during OGTT and fasting insulin. Bland–Altman analysis revealed a good relationship between the M value and PREDIM in the validation dataset (only 9 of 154 observations outside limits of agreement). Also, no significant differences were found between the M value and PREDIM (equivalence test: p?<?0.0063). Subgroup stratification showed that measured M value and PREDIM have a similar ability to detect intergroup differences (p?<?0.02, both M value and PREDIM).

Conclusions/interpretation

The new index PREDIM provides excellent prediction of M values from OGTT or meal data, thereby allowing comparison of insulin sensitivity between studies using different tests.

     

Impact of daily incremental change in environmental temperature on beta cell function and the risk of gestational diabetes in pregnant women

Aims/hypothesis

The prevalence of gestational diabetes (GDM) is higher in summer months, possibly reflecting an association between ambient temperature and blood glucose levels. However, the specific exposure and mechanism by which temperature may affect glucose metabolism in pregnancy remains unclear. We systematically evaluated the relationships of environmental temperature and changes therein over varying durations of exposure time with beta cell function, insulin sensitivity and glucose tolerance in women undergoing antepartum screening for GDM.

Methods

At a mean gestation of 29 weeks, 1464 women in Toronto (ON, Canada) underwent an OGTT, from which 318 were diagnosed with GDM. Blood glucose, beta cell function and insulin sensitivity were evaluated in relation to 18 temperature variables: mean temperature and change in temperature on the day of the OGTT and over the preceding 7, 14, 21, 28, 35, 42, 49 and 56 days, respectively.

Results

Temperature changes in the preceding 14, 21, 28, 35, 42, 49 and 56 days (rather than mean temperatures) emerged as independent predictors of blood glucose. These relationships were evident in months where mean daily temperature was rising (February – July), but not in those where it was falling (August – January). Indeed, in February – July, the temperature changes in the preceding 21, 28 and 35 days emerged as predictors of both poorer beta cell function and higher blood glucose. Moreover, in February – July, the changes in temperature in the preceding 21 days (OR 1.16, 95% CI 1.01, 1.33) and 28 days (OR 1.20, 95% CI 1.03, 1.39) were independent predictors of GDM, while mean temperatures were not.

Conclusions/interpretation

In pregnant women, rising environmental temperature in the 3–4 weeks prior to glucose tolerance testing may be associated with beta cell dysfunction and an increased risk of GDM.

     

Biopsychosocial Factors Associated With Satisfaction and Sustained Use of Artificial Pancreas Technology and Its Components: a Call to the Technology Field

Purpose of Review

Summarize biopsychosocial factors associated with using continuous glucose monitors (CGMs), insulin pumps, and artificial pancreas (AP) systems and provide a “call to the field” about their importance to technology uptake and maintained use.

Recent Findings

Insulin pumps and CGMs are becoming standard of care for individuals with type 1 diabetes (T1D). AP systems combining a CGM, insulin pump, and automated dosing algorithm are available for commercial use. Despite improved glycemic control with AP system use, numerous barriers exist which may limit their benefit. Studies on components of AP systems (pumps, CGMs) are limited and demonstrate mixed results of their impact on fear of hypoglycemia, adherence, quality of life, depression and anxiety, and diabetes distress. Studies examining biopsychological factors associated specifically with sustained use of AP systems are also sparse.

Summary

Biological, psychological and social impacts of AP systems have been understudied and the information they provide has not been capitalized upon.

     

Glycemic Outcomes of Islet Autotransplantation

Purpose of Review

While there has been a growing utilization of total pancreatectomy with islet autotransplantation (TPIAT) for patients with medically refractory chronic pancreatitis over the past few decades, there remains a lack of consensus clinical guidelines to inform the counseling and management of patients undergoing TPIAT. In this article, we review the current clinical practice and published experience of several TPIAT centers, outline key aspects in managing patients undergoing TPIAT, and discuss the glycemic outcomes of this procedure.

Recent Findings

Aiming for lower inpatient glucose targets immediately after surgery (usually 100–120 mg/dl), maintaining all patients on subcutaneous insulin for at least 3 months to “rest” islets before an attempt is made to wean insulin, and close outpatient endocrinology follow-up after TPIAT particularly in the first year is common and related to better outcomes. Although TPIAT procedures and glycemic outcomes may differ across surgical centers, overall, approximately one third of patients are insulin independent at 1 year after TPIAT. Higher islet yield and lower preoperative glucose levels are among the strongest predictors of short-term post-operative insulin independence. Beyond 1 year post-operatively, the clinical management and long-term glycemic outcomes of patients after TPIAT are more variable.

Summary

A multidisciplinary approach is essential in optimizing the preoperative, inpatient, and post-operative management and counseling of patients about the expected glycemic outcomes after surgery. Consensus guidelines for the clinical management of diabetes after TPIAT and harmonization of data collection protocols among TPIAT centers are needed to address the current knowledge gaps in clinical care and research and to optimize glycemic outcomes after TPIAT.

     

Gestational retinal microvasculature and the risk of 5 year postpartum abnormal glucose metabolism

Aims/hypothesis

Changes in retinal microvasculature may reflect insulin resistance. We examined the association of changes in retinal microvasculature during pregnancy and risk of subsequent abnormal glucose metabolism in a cohort of mothers at baseline and 5 years postpartum.

Methods

Of the participants from the Singapore birth cohort (Growing Up in Singapore Towards Healthy Outcomes [GUSTO]), 276 mothers attended both baseline (at 26–28 weeks of gestation) and follow-up (5 year postpartum) visits. At baseline we performed retinal photography and assessed retinal microvascular variables using a validated grading system. At follow-up, we assessed glucose tolerance using a 75 g OGTT. We defined abnormal glucose metabolism if participants: (1) had onset of gestational diabetes mellitus (GDM) in subsequent pregnancies within a 5 year follow-up period (n = 103) or (2) had prediabetes (impaired fasting glucose, impaired glucose tolerance or HbA_1c 5.7–6.4% [39–46 mmol/mol]) and diabetes diagnosed at the 5 year follow-up visit (n = 84), according to WHO guidelines.

Results

The incidence of GDM in subsequent pregnancy and abnormal glucose metabolism 5 years postpartum was 25.2% and 30.4%, respectively. Each 10 μm widening in retinal venular calibre was associated with a significant risk of postpartum abnormal glucose metabolism (RR 1.2 [95% CI 1.0, 1.5]), independent of maternal age, college education, ethnicity, pre-pregnancy BMI and GDM at baseline. Narrower retinal arteriolar calibre and venular branching angle at baseline was associated with a higher insulin resistance index (1.4 [95% CI 1.1, 1.7] and 1.3 [95% CI 1.1, 1.6], respectively) at follow-up.

Conclusions/interpretation

Retinal microvasculature in pregnant women was associated with abnormal glucose metabolism 5 years postpartum. Alteration of microvascular structure during pregnancy may signal subclinical changes that underlie the development of prediabetes and diabetes.

     

Altered Gut Microbiota in Type 2 Diabetes: Just a Coincidence?

Purpose of Review

In the last decade many studies have suggested an association between the altered gut microbiota and multiple systemic diseases including diabetes. In this review, we will discuss potential pathophysiological mechanisms, the latest findings regarding the mechanisms linking gut dysbiosis and type 2 diabetes (T2D), and the results obtained with experimental modulation of microbiota.

Recent Findings

In T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control.

Summary

Evidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.