IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.

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Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00014.2015 ◽

2015 ◽

Vol 308 (12) ◽

pp. E1106-E1115 ◽

Cited By ~ 33

Author(s):

Ashwini Mallad ◽

Ling Hinshaw ◽

Michele Schiavon ◽

Chiara Dalla Man ◽

Vikash Dadlani ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glucose Metabolism ◽

Insulin Pump ◽

Postprandial Glucose ◽

Insulin Pump Therapy ◽

Moderate Intensity ◽

Glucose Turnover ◽

Moderate Intensity Exercise ◽

Pump Therapy

To determine the effects of exercise on postprandial glucose metabolism and insulin action in type 1 diabetes (T1D), we applied the triple tracer technique to study 16 T1D subjects on insulin pump therapy before, during, and after 75 min of moderate-intensity exercise (50% V̇o2max) that started 120 min after a mixed meal containing 75 g of labeled glucose. Prandial insulin bolus was administered as per each subject's customary insulin/carbohydrate ratio adjusted for meal time meter glucose and the level of physical activity. Basal insulin infusion rates were not altered. There were no episodes of hypoglycemia during the study. Plasma dopamine and norepinephrine concentrations rose during exercise. During exercise, rates of endogenous glucose production rose rapidly to baseline levels despite high circulating insulin and glucose concentrations. Interestingly, plasma insulin concentrations increased during exercise despite no changes in insulin pump infusion rates, implying increased mobilization of insulin from subcutaneous depots. Glucagon concentrations rose before and during exercise. Therapeutic approaches for T1D management during exercise will need to account for its effects on glucose turnover, insulin mobilization, glucagon, and sympathetic response and possibly other blood-borne feedback and afferent reflex mechanisms to improve both hypoglycemia and hyperglycemia.

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Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA

Clinical Diabetes and Endocrinology ◽

10.1186/s40842-021-00135-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Maria Månsson Martinez ◽

Lampros Spiliopoulos ◽

Falastin Salami ◽

Daniel Agardh ◽

Jorma Toppari ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glucose Metabolism ◽

Beta Cell ◽

Beta Cell Function ◽

Glucose Tolerance Test ◽

Cell Function ◽

Fasting Glucose ◽

Tolerance Test ◽

Islet Autoantibodies

Abstract Background Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone. Methods Subjects (n = 57) at 2–50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24). Results Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2–4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was − 1.88 (− 2.71, − 1.05) p = 3.49 × 10–5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (− 0.80 (− 1.58, − 0.02), p = 0.046). Conclusions The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. Trial registration ClinicalTrials.gov identifier: NCT02605148, November 16, 2015

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Heterogeneity of Beta-cell Function in Subjects With Multiple Islet Autoantibodies in the TEDDY Family Prevention Study - TEFA

10.21203/rs.3.rs-702763/v1 ◽

2021 ◽

Author(s):

Maria Cecilia Månsson Martinez ◽

Lampros Spiliopoulos ◽

Falastin Salami ◽

Daniel Agardh ◽

Jorma Toppari ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glucose Metabolism ◽

Beta Cell ◽

Beta Cell Function ◽

Glucose Tolerance Test ◽

Cell Function ◽

Glucose Monitoring ◽

Tolerance Test ◽

Islet Autoantibodies

Abstract BackgroundIndividuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial one month apart for beta-cell function, glucose metabolism and continuous glucose monitoring. We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and continuous glucose monitoring (CGM) allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.MethodsSubjects (n=57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed one month later by OGTT, and one week of CGM (n=24).ResultsAutoantibodies against GAD65 (GADA; n=52), ZnT8 (ZnT8A; n=40), IA-2 (IA-2A; n=38) and insulin (IAA; n=28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2(FPIR) as the outcome and log2(OGTT glucose AUC) as the predictor, adjusting for age and sex was -1.88 (-2.71, -1.05) p = 3.49x10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W)A was associated with a lower log2-transformed FPIR (-0.80 (-1.58, -0.02), p = 0.046). Conclusions The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. Trial registrationClinicalTrials.gov identifier: NCT02605148, November 16, 2015, https://clinicaltrials.gov/ct2/show/nct02605148

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